Science.gov

Sample records for lung cancer growth

  1. Quercetin suppresses lung cancer growth by targeting Aurora B kinase.

    PubMed

    Xingyu, Zhu; Peijie, Ma; Dan, Peng; Youg, Wang; Daojun, Wang; Xinzheng, Chen; Xijun, Zhang; Yangrong, Song

    2016-11-01

    aurora B kinase is highly expressed in several cancer cells and promotes tumorigenesis and progression, and therefore, it is an important target for drug to treat tumors. Quercetin was identified to be an antitumor agent. Herein, we report for the first time that quercetin inhibited aurora B activities by directly binding with aurora B in vitro and in vivo. Ex vivo studies showed that quercetin inhibited aurora B activities in JB6 Cl41 cells and A549 lung cancer cells. Moreover, knockdown of aurora B in A549 cells decreased their sensitivities to quercetin. In vivo study demonstrated that injection of quercetin in A549 tumor-bearing mice effectively suppressed cancer growth. The phosphorylation of histone 3 in tumor tissues was also decreased after quercetin treatment. In short, quercetin can suppress growth of lung cancer cells as an aurora B inhibitor both in vitro and in vivo.

  2. 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.

  3. Epidermal growth factor receptor mutation enhances expression of vascular endothelial growth factor in lung cancer.

    PubMed

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

    2016-12-01

    Epidermal growth factor receptor (EGFR) activation has been demonstrated to have a critical role in tumor angiogenesis. In the present study, the correlation between EGFR mutations and vascular endothelial growth factor (VEGF) was investigated in lung cancer cell lines and non-small-cell lung cancer (NSCLC) tumor tissues. VEGF levels were significantly increased in culture medium of lung cancer cells and NSCLC tissues with EGFR mutations (H1650 vs. A549, P=0.0399; H1975 vs. A549, P<0.0001). Stable lung cancer cell lines expressing mutant (exon 19 deletion, E746-A750; exon 21 missense mutation, L858R) and wild-type EGFR genes were established. Significantly increased expression of VEGF and stronger inhibitory effects of gefitinib to VEGF expression were observed in exon 19 deletion stable lung cancer cells (exon 19 deletion vs. wild-type EGFR, P=0.0005). The results of the present study may provide an insight into the association of mutant EGFR and VEGF expression in lung cancer, and may assist with further development of targeted therapy for NSCLC in the future.

  4. Differential roles of STAT3 in the initiation and growth of lung cancer.

    PubMed

    Zhou, J; Qu, Z; Yan, S; Sun, F; Whitsett, J A; Shapiro, S D; Xiao, G

    2015-07-01

    Signal transducer and activator of transcription 3 (STAT3) is linked to multiple cancers, including pulmonary adenocarcinoma. However, the role of STAT3 in lung cancer pathogenesis has not been determined. Using lung epithelial-specific inducible knockout strategies, we demonstrate that STAT3 has contrasting roles in the initiation and growth of both chemically and genetically induced lung cancers. Selective deletion of lung epithelial STAT3 in mice before cancer induction by the smoke carcinogen, urethane, resulted in increased lung tissue damage and inflammation, K-Ras oncogenic mutations and tumorigenesis. Deletion of lung epithelial STAT3 after establishment of lung cancer inhibited cancer cell proliferation. Simultaneous deletion of STAT3 and expression of oncogenic K-Ras in mouse lung elevated pulmonary injury, inflammation and tumorigenesis, but reduced tumor growth. These studies indicate that STAT3 prevents lung cancer initiation by maintaining pulmonary homeostasis under oncogenic stress, whereas it facilitates lung cancer progression by promoting cancer cell growth. These studies also provide a mechanistic basis for targeting STAT3 to lung cancer therapy.

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

    PubMed

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

    2016-07-01

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

  7. A novel anticancer agent SNG1153 inhibits growth of lung cancer stem/progenitor cells

    PubMed Central

    Wang, Jing; Zhu, Hai; Han, Yuqing; Jin, Mingji; Wang, Jun; Zhou, Congya; Ma, Junfeng; Lin, Qingcong; Wang, Zhaoyi; Meng, Kun; Fu, Xueqi

    2016-01-01

    Lung cancer is the leading cause of cancer-related death in both men and women. Lung cancer contains a small population of cancer cells with stem-like features known as cancer stem cells (CSCs). CSCs are often more resistant to current therapeutic treatments. Thus, it is urgent to develop a novel agent that is able to inhibit CSCs growth. In this study, we examined the ability of SNG1153, a novel chemical agent to inhibit the growth of lung CSCs. We found that SNG1153 inhibited growth and induced apoptosis in established lung cancer cells. We also found that SNG1153 inhibited the tumorsphere formation and decreased CD133-positive (lung CSC marker) cancer cells. SNG1153 was able to attenuate tumor formation in NOD/SCID (non-obese diabetic/severe combined immunodeficient) mice injected with lung tumorsphere cells. We further demonstrated that SNG1153 induced β-catenin phosphorylation and down-regulated β-catenin. Our results thus demonstrate that SNG1153 effectively inhibits the growth of lung CSCs and suggest that SNG1153 may be a novel therapeutic agent to treat human lung cancer. PMID:27281614

  8. Lung Cancer

    MedlinePlus

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

  9. What Is Lung Cancer?

    MedlinePlus

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

  10. Lung Cancer

    MedlinePlus

    ... has been a steady drop in lung cancer deaths among men, mainly because fewer men are smoking, and since the turn of the century, lung cancer deaths in women have been slowly declining. Cigarette smoking rates had been dropping steadily in the 1990s ...

  11. Correlation of genetic polymorphism of vascular endothelial growth factor gene with susceptibility to lung cancer.

    PubMed

    Liu, C; Zhou, X; Gao, F; Qi, Z; Zhang, Z; Guo, Y

    2015-06-01

    The aim of the study is to study the correlation of genetic polymorphism of vascular endothelial growth factor (VEGF) gene with susceptibility to primary lung cancer. A total of 414 patients with primary lung cancer and 338 healthy volunteers were enrolled in this case-control study from September 2008 to October 2011. Gene identification with PCR-RFLP (polymerase chain reaction-based restriction fragment length polymorphism) was used to detect in white blood cells from the subjects the single-nucleotide polymorphisms (SNP) of VEGF gene, including +405G/C, -460 T/C, -1154G/A, -2578C/A sites. Association of genotypes or haplotypes with susceptibility of lung cancer was analyzed with unconditional logistic regression adjusted by gender and age. Smoking was significantly associated with increased risk of lung cancer. Gene phenotypic analysis demonstrated that C allele of +405G/C in VEGF gene was significantly associated increased risk of lung cancer in males (P=0.0094, odds ratio=1.634.3), as that with carrying GCTC haplotype (odds ratio=1.349), whereas carrying GACG had decreased risk for lung cancer (odds ratio=0.044). No relationship existed between 460 T/C, -1154G/A, -2578C/A alleles of VEGF gene and risk of lung cancer. VEGF gene polymorphism may have a role in the development of lung cancer.

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

    PubMed

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

    2016-01-01

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

  13. Regulation of brachyury by fibroblast growth factor receptor 1 in lung cancer

    PubMed Central

    Hu, Yunping; Feng, Xin; Mintz, Akiva; Petty, W. Jeffrey; Hsu, Wesley

    2016-01-01

    Recent evidence suggests that T-box transcription factor brachyury plays an important role in lung cancer development and progression. However, the mechanisms underlying brachyury-driven cellular processes remain unclear. Here we found that fibroblast growth factor receptor 1/mitogen-activated protein kinase (FGFR1/MAPK) signaling regulated brachyury in lung cancer. Analysis of FGFR1-4 and brachyury expression in human lung tumor tissue and cell lines found that only expression of FGFR1 was positively correlated with brachyury expression. Specific knockdown of FGFR1 by siRNA suppressed brachyury expression and epithelial–mesenchymal transition (EMT) (upregulation of E-cadherin and β-catenin and downregulation of Snail and fibronectin), whereas forced overexpression of FGFR1 induced brachyury expression and promoted EMT in lung cancer cells. Activation of fibroblast growth factor (FGF)/FGFR1 signaling promoted phosphorylated MAPK extracellular signal-regulated kinase (ERK) 1/2 translocation from cytoplasm to nucleus, upregulated brachyury expression, and increased cell growth and invasion. In addition, human lung cancer cells with higher brachyury expression were more sensitive to inhibitors targeting FGFR1/MAPK pathway. These findings suggest that FGFR1/MAPK may be important for brachyury activation in lung cancer, and this pathway may be an appealing therapeutic target for a subset of brachyury-driven lung cancer. PMID:27893433

  14. Role of epidermal growth factor receptor in lung cancer and targeted therapies

    PubMed Central

    Liu, Tie-Cheng; Jin, Xin; Wang, Yan; Wang, Ke

    2017-01-01

    Lung cancer is the foremost cause of cancer-related deaths world-wide. Both, the major forms of lung cancer, Non-small cell lung cancer (NSCLC) and Small cell lung cancers (SCLC), have responded effectively to chemo-, radiation and adjuvant-therapies. Tumor removal through surgery also appeared as a good therapeutic strategy. However, these therapies demonstrated unfavourable side-effects, and hence novel drugs targeting lung cancer emerged essential. Activation of epidermal growth factor receptor (EGFR)-tyrosine kinases is a key reason for lung cancer progression. Two important strategies that have attenuated lung cancers were through treatments with EGFR-tyrosine kinase-inhibitors, erlotinib and gefitinib, or EGFR-neutralizing antibodies, cetuximab and bevacizumab. A major advantage with erlotinib and gefitinib was their role in second and third-line treatments following chemotherapies. Phase II/III clinical trials showed that combinatorial treatment of tyrosine kinase (TK)-inhibitors with chemotherapeutics, such as docetaxel and pemetrexed, caused significant improvements in progression-free survival and overall survival.Phase I and II clinical studies also revealed that combination of tyrosine kinase-inhibitors with the EGFR-targeted antibodies was an effective approach for treating lung cancer. However, patients having T790M-mutations within EGFR gene were resistant to erlotinib and gefitinib. Alternatively, another second-generation EGFR-tyrosine kinase-inhibitor, afatinib, that could circumvent the problem of drug resistance has been developed as lung cancer therapy. The current review focuses on the role of EGFR in lung cancer progression and apprises about the EGFR-targeted therapies. The review also informs on the adverse side-effects of these therapies and enlightens the need for safer therapeutic regimens to eradicate this dreaded disease. PMID:28337370

  15. 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.

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

    DOE PAGES

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

    2014-11-21

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

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

    PubMed

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

    2005-10-25

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

  18. Epidermal growth factor receptor and KRAS mutations in Brazilian lung cancer patients

    PubMed Central

    Bacchi, Carlos E.; Ciol, Heloísa; Queiroga, Eduardo M.; Benine, Lucimara C.; Silva, Luciana H.; Ojopi, Elida B.

    2012-01-01

    OBJECTIVE: Epidermal growth factor receptor is involved in the pathogenesis of non-small cell lung cancer and has recently emerged as an important target for molecular therapeutics. The KRAS oncogene also plays an important role in the development of lung cancer. The aim of this study was to evaluate the frequency of epidermal growth factor receptor and KRAS mutations in a population of Brazilian patients with non-small cell lung cancer. METHODS: A total of 207 specimens from Brazilian patients with non-small cell lung cancer were analyzed for activating epidermal growth factor receptor and KRAS somatic mutations, and their associations with clinicopathological characteristics (including age, gender, ethnicity, smoking habits, and histological subtype) were examined. RESULTS: We identified 63 cases (30.4%) with epidermal growth factor receptor mutations and 30 cases (14.6%) with KRAS mutations. The most frequent epidermal growth factor receptor mutation we detected was a deletion in exon 19 (60.3%, 38 patients), followed by an L858R amino acid substitution in exon 21 (27%, 17 patients). The most common types of KRAS mutations were found in codon 12. There were no significant differences in epidermal growth factor receptor or KRAS mutations by gender or primary versus metastatic lung cancer. There was a higher prevalence of KRAS mutations in the non-Asian patients. Epidermal growth factor receptor mutations were more prevalent in adenocarcinomas than in non-adenocarcinoma histological types. Being a non-smoker was significantly associated with the prevalence of epidermal growth factor receptor mutations, but the prevalence of KRAS mutations was significantly associated with smoking. CONCLUSIONS: This study is the first to examine the prevalence of epidermal growth factor receptor and KRAS mutations in a Brazilian population sample with non-small cell lung cancer. PMID:22666783

  19. 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 ...

  20. RFPL3 and CBP synergistically upregulate hTERT activity and promote lung cancer growth

    PubMed Central

    Yu, Wendan; Cai, Xin; Dai, Meng; Xu, Tingting; Huang, Wenlin; Guo, Wei; Deng, Wuguo; Wu, Taihua

    2015-01-01

    hTERT is the key component of telomerase and its overactivation contributes to maintaining telomere length and cell immortalization. Previously, we identified RFPL3 as a new transcription activator of hTERT in lung cancers. However, the exact mechanism of RFPL3 in mediating hTERT activation and its associated signal regulatory network remain unclear. In this study, we found that RFPL3 colocalized and interacted directly with CBP in the nucleus of lung cancer cells. Immunohistochemical analysis of tissue microarrays of lung cancers revealed the simultaneous overexpression of both RFPL3 and CBP predicted relatively poor prognosis. Furthermore, we confirmed their synergistic stimulation on hTERT expression and tumor cell growth. The binding of RFPL3 to hTERT promoter was reduced markedly when CBP was knocked down by its specific siRNA or suppressed by its inhibitor in lung cancer cells with stable overexpression of RFPL3. When one of the two proteins RFPL3 and CBP was upregulated or downregulated, whereas the another remains unchanged, hTERT expression and telomerase activity were activated or repressed accordingly. In the meantime, the growth of lung cancer cells was also promoted or attenuated accordingly. Furthermore, we also found that RFPL3 coordinated with CBP to upregulate hTERT through the CBP-induced acetylation of RFPL3 protein and their co-anchoring at hTERT promoter region. Collectively, our results reveal a new mechanism of hTERT regulation in lung cancer cells and suggest the RFPL3/CBP/hTERT signaling pathway may be a new targets for lung cancer treatment. PMID:26318425

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

    PubMed

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

    2009-03-15

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

  2. 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.

  3. IL-15/sIL-15Rα gene transfer suppresses Lewis lung cancer growth in the lungs, liver and kidneys.

    PubMed

    Sun, H; Liu, D

    2016-01-01

    Nearly 40% of people with lung cancer have tumor growth in other organs at the time of diagnosis. Current treatment strategies for patients with late-stage lung cancer are primarily palliative and only showed modest efficacy. The current study takes advantage of the hydrodynamic gene delivery technique to evaluate the antitumor activity of interleukin (IL)-15/sIL-15Rα on lung tumors growing in the lungs, liver and kidneys. We demonstrate that hydrodynamic tail vein injection of 2 μg of AG209 DP muIL-15sRα+IL-15 plasmid resulted in serum IL-15/sIL-15Rα reaching a peak level of ~10 μg ml(-1) 1 day after the injection and gradually declined to ~5 ng ml(-1) within 3 days. Quantitative PCR analysis revealed that overexpression of IL-15/sIL-15Rα induced the activation of natural killer and T cells, evidenced by increased mRNA levels of marker genes including granzyme B, perforin, Ifn-γ, T-bet and Cd8 in the lungs, liver and kidneys. Importantly, transfer of the Il-15/sIl-15Rα gene alone, or in combination with gemcitabine chemotherapy, significantly inhibited the tumor growth in these three organs and prolonged median survival time of treated mice by 1.7- and 3.3-fold, respectively. The therapeutic benefits are principally blockade and elimination of tumor growth in the liver and kidneys. Taken together, these results suggest that IL-15/sIL-15Rα-based gene therapy could be an effective approach to treat late-stage lung cancer with metastases in other organs.

  4. 6 Common Cancers - Lung Cancer

    MedlinePlus

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

  5. Vav1 promotes lung cancer growth by instigating tumor-microenvironment cross-talk via growth factor secretion.

    PubMed

    Sebban, Shulamit; Farago, Marganit; Rabinovich, Shiran; Lazer, Galit; Idelchuck, Yulia; Ilan, Lena; Pikarsky, Eli; Katzav, Shulamit

    2014-10-15

    Vav1 is a signal transducer that functions as a scaffold protein and a regulator of cytoskeleton organization in the hematopoietic system, where it is exclusively expressed. Recently, Vav1 was shown to be involved in diverse human cancers, including lung cancer. We demonstrate that lung cancer cells that abnormally express Vav1 secrete growth factors in a Vav1-dependent manner. Transcriptome analysis demonstrated that Vav1 depletion results in a marked reduction in the expression of colony-stimulating-factor-1 (CSF1), a hematopoietic growth factor. The association between Vav1 expression and CSF1 was further supported by signal transduction experiments, supporting involvement of Vav1 in regulating lung cancer secretome. Blocking of ERK phosphorylation, led to a decrease in CSF1 transcription, thus suggesting a role for ERK, a downstream effector of Vav1, in CSF1 expression. CSF1-silenced cells exhibited reduced focus formation, proliferation abilities, and growth in NOD/SCID mice. CSF1-silenced H358 cells resulted in significantly smaller tumors, showing increased fibrosis and a decrease in tumor infiltrating macrophages. Finally, immunohistochemical analysis of primary human lung tumors revealed a positive correlation between Vav1 and CSF1 expression, which was associated with tumor grade. Additional results presented herein suggest a potential cross-talk between cancer cells and the microenvironment controlled by CSF1/Vav1 signaling pathways.

  6. Vav1 promotes lung cancer growth by instigating tumor-microenvironment cross-talk via growth factor secretion

    PubMed Central

    Rabinovich, Shiran; Lazer, Galit; Idelchuck, Yulia; Ilan, Lena; Pikarsky, Eli; Katzav, Shulamit

    2014-01-01

    Vav1 is a signal transducer that functions as a scaffold protein and a regulator of cytoskeleton organization in the hematopoietic system, where it is exclusively expressed. Recently, Vav1 was shown to be involved in diverse human cancers, including lung cancer. We demonstrate that lung cancer cells that abnormally express Vav1 secrete growth factors in a Vav1-dependent manner. Transcriptome analysis demonstrated that Vav1 depletion results in a marked reduction in the expression of colony-stimulating-factor-1 (CSF1), a hematopoietic growth factor. The association between Vav1 expression and CSF1 was further supported by signal transduction experiments, supporting involvement of Vav1 in regulating lung cancer secretome. Blocking of ERK phosphorylation, led to a decrease in CSF1 transcription, thus suggesting a role for ERK, a downstream effector of Vav1, in CSF1 expression. CSF1-silenced cells exhibited reduced focus formation, proliferation abilities, and growth in NOD/SCID mice. CSF1-silenced H358 cells resulted in significantly smaller tumors, showing increased fibrosis and a decrease in tumor infiltrating macrophages. Finally, immunohistochemical analysis of primary human lung tumors revealed a positive correlation between Vav1 and CSF1 expression, which was associated with tumor grade. Additional results presented herein suggest a potential cross-talk between cancer cells and the microenvironment controlled by CSF1/Vav1 signaling pathways. PMID:25313137

  7. Epidermal Growth Factor Receptor Mutated Advanced Non-Small Cell Lung Cancer: A Changing Treatment Paradigm.

    PubMed

    Pakkala, Suchita; Ramalingam, Suresh S

    2017-02-01

    Activating mutations in the epidermal growth factor receptor (EGFR) are present in approximately 15% of US patients with lung adenocarcinoma. EGFR tyrosine kinase inhibitors are associated with high response rate and progression-free survival for patients with non-small cell lung cancer with this genotype. Gefitinib, erlotinib, and afatinib are the EGFR tyrosine kinase inhibitors that are presently in clinical use. Understanding resistance mechanisms has led to the identification of a secondary mutational target, T790M, in more than half of patients, for which osimertinib has been approved. This article reviews the current treatments, resistance mechanisms, and strategies to overcome resistance.

  8. [Effects of green tea on growth inhibition and immune regulation of Lewis lung cancer in mice].

    PubMed

    Zhu, M; Gong, Y; Ge, G

    1997-11-01

    C57/BL6J mice were inoculated with Lewis lung cancer cells as an experimental model to study the effects of green tea on cancer prevention, inhibition of tumor growth and immune regulation in mice with tumor. Results showed that weight of thymus in C57/BL6J mice and its index declined, proportion of positive CD4 subgroup of T lymphocyte and ratio of CD4+, to CD8+ reduced, baseline chemilumi-nescence decreased in peripheral white blood cells, yeast zymosan stimulated chemiluminescence increased, and number of immunoglobulin M formation cells decreased. It indicated that green tea had obvious inhibition in Lewis lung cancer and protective effects, to various extent, on adverse changes of above indices.

  9. TIPE2 Inhibits Lung Cancer Growth Attributing to Promotion of Apoptosis by Regulating Some Apoptotic Molecules Expression

    PubMed Central

    Liu, Qing-Qing; Zhang, Feng-Feng; Wang, Fang; Qiu, Jing-Hua; Luo, Chun-Hua; Zhu, Guo-Yong; Liu, Ying-Fu

    2015-01-01

    Recent studies found that TIPE2 was involved in cancer development. However, little is known about TIPE2 in lung cancer. Our study aims to clarify the role of TIPE2 in lung carcinogenesis. We examined the expression of TIPE2 in lung squamous cancer (LSC), small cell lung cancer and lung adenocarcinoma (AdC) tissues and found that TIPE2 expression was lost in small cell lung cancer, compared with adjacent non-tumor tissues. Overexpression of TIPE2 significantly inhibited the growth of lung cancer cell H446 in vitro and even suppressed tumor formation in vivo. Flow cytometry analysis found TIPE2 overexpression promoted apoptosis of H446. In TIPE2 over-expression cells, caspase-3, caspase-9, and Bax were significantly up-regulated while Bcl-2 was down-regulated. Moreover, coincident results were shown by immunohistochemistry in tumors from nude mice. TIPE2 inhibited the phosphorylation of Akt, while promoting the phosphorylation of P38, but had no effect on IκBα and ERK pathway. Taken together, TIPE2 promoted lung cancer cell apoptosis through affecting apoptosis-related molecules caspase-3, caspase-9, Bcl-2 and Bax, possibly via regulating P38 and Akt pathways, indicating that TIPE2 might be a novel marker for lung cancer diagnosis and therapy. PMID:25946186

  10. Lung Cancer Biomarkers.

    PubMed

    Villalobos, Pamela; Wistuba, Ignacio I

    2017-02-01

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

  11. MicroRNA-221 promotes human non-small cell lung cancer cell H460 growth.

    PubMed

    Xu, Yiming; Zhong, Chongjun; Ding, Shengguang; Huang, Haitao; Shen, Zhenya

    2015-01-01

    MicroRNA (miRNA-221) has been reported to be a regulator of cell proliferation. Here we intended to investigate the role of miRNA-221 in regulating the growth of human non-small cell lung cancer cell line H460. H460 cells were transfected with miRNA-221 mimics/inhibitors or their respective negative controls. Real-time quantitative PCRs (qRT-PCRs) were used to confirm the effects of miRNA-221 mimics and inhibitors in H460 cells while Cell Counting Kit 8 (CCK-8) and 5-Ethynyl-2'-deoxyuridine (EdU) assay were used to access the cell viability and proliferation. P27 and P57, as putative targets of miRNA-221, were determined by qRT-PCRs in H460 cells. We found that overexpression of miRNA-221 led to increased proliferative rate and cell viability in H460 cells while down-regulation of miRNA-221 decreased those effects. P27 but not P57 was identified as a potential target gene of miRNA-221 in H460 as P27 was negatively regulated by miRNA-221 in the protein level. In conclusion, this study suggests that miRNA-221 controls human non-small cell lung cancer cell H460 growth potentially by targeting P57. Inhibition of miRNA-221 represents a novel potential treatment for human non-small cell lung cancer.

  12. Early Growth Response-1 Induces and Enhances Vascular Endothelial Growth Factor-A Expression in Lung Cancer Cells

    PubMed Central

    Shimoyamada, Hiroaki; Yazawa, Takuya; Sato, Hanako; Okudela, Koji; Ishii, Jun; Sakaeda, Masashi; Kashiwagi, Korehito; Suzuki, Takehisa; Mitsui, Hideaki; Woo, Tetsukan; Tajiri, Michihiko; Ohmori, Takahiro; Ogura, Takashi; Masuda, Munetaka; Oshiro, Hisashi; Kitamura, Hitoshi

    2010-01-01

    Vascular endothelial growth factor-A (VEGF-A) is crucial for angiogenesis, vascular permeability, and metastasis during tumor development. We demonstrate here that early growth response-1 (EGR-1), which is induced by the extracellular signal–regulated kinase (ERK) pathway activation, activates VEGF-A in lung cancer cells. Increased EGR-1 expression was found in adenocarcinoma cells carrying mutant K-RAS or EGFR genes. Hypoxic culture, siRNA experiment, luciferase assays, chromatin immunoprecipitation, electrophoretic mobility shift assays, and quantitative RT-PCR using EGR-1–inducible lung cancer cells demonstrated that EGR-1 binds to the proximal region of the VEGF-A promoter, activates VEGF-A expression, and enhances hypoxia inducible factor 1α (HIF-1α)-mediated VEGF-A expression. The EGR-1 modulator, NAB-2, was rapidly induced by increased levels of EGR-1. Pathology samples of human lung adenocarcinomas revealed correlations between EGR-1/HIF-1α and VEGF-A expressions and relative elevation of EGR-1 and VEGF-A expression in mutant K-RAS- or EGFR-carrying adenocarcinomas. Both EGR-1 and VEGF-A expression increased as tumors dedifferentiated, whereas HIF-1α expression did not. Although weak correlation was found between EGR-1 and NAB-2 expressions on the whole, NAB-2 expression decreased as tumors dedifferentiated, and inhibition of DNA methyltransferase/histone deacetylase increased NAB-2 expression in lung cancer cells despite no epigenetic alteration in the NAB-2 promoter. These findings suggest that EGR-1 plays important roles on VEGF-A expression in lung cancer cells, and epigenetic silencing of transactivator(s) associated with NAB-2 expression might also contribute to upregulate VEGF-A expression. PMID:20489156

  13. Lentivirus-mediated knockdown of NLK inhibits small-cell lung cancer growth and metastasis

    PubMed Central

    Lv, Mutian; Li, Yaming; Tian, Xin; Dai, Shundong; Sun, Jing; Jin, Guojiang; Jiang, Shenyi

    2016-01-01

    Nemo-like kinase (NLK), an evolutionarily conserved serine/threonine kinase, has been recognized as a critical regulator of various cancers. In this study, we investigated the role of NLK in human small-cell lung cancer (SCLC), which is the most aggressive form of lung cancer. NLK expression was evaluated by quantitative real-time polymerase chain reaction in 20 paired fresh SCLC tissue samples and found to be noticeably elevated in tumor tissues. Lentivirus-mediated RNAi efficiently suppressed NLK expression in NCI-H446 cells, resulting in a significant reduction in cell viability and proliferation in vitro. Moreover, knockdown of NLK led to cell cycle arrest at the S-phase via suppression of Cyclin A, CDK2, and CDC25A, which could contribute to cell growth inhibition. Furthermore, knockdown of NLK decreased the migration of NCI-H446 cells and downregulated matrix metalloproteinase 9. Treatment with NLK short hairpin RNA significantly reduced SCLC tumor growth in vivo. In conclusion, this study suggests that NLK plays an important role in the growth and metastasis of SCLC and may serve as a potential therapeutic target for the treatment of SCLC. PMID:27895463

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

    PubMed

    Yu, Jing Jing; Zhou, Long Dian; Zhao, Tian Tian; Bai, Wei; Zhou, Jing; Zhang, Wei

    2015-09-01

    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.

  15. Salvianolic acid A positively regulates PTEN protein level and inhibits growth of A549 lung cancer cells

    PubMed Central

    BI, LEI; CHEN, JIANPING; YUAN, XIAOJING; JIANG, ZEQUN; CHEN, WEIPING

    2013-01-01

    Salvianolic acid A (Sal A) is an effective compound extracted from Salvia miltiorrhiza which has been used in the treatment of various diseases. Preliminary data indicate that Sal A treatment has a specific anti-lung cancer effect. However, the manner in which Sal A regulates cancer growth remains unknown. In this study, the A549 lung cancer cell line and its response to Sal A treatment was examined. Results showed that Sal A treatment significantly decreased A549 cell growth, promoted partial apoptosis and increased mitochondrial membrane permeability. Western blot analysis showed that Sal A upregulated the phosphatase and tensin homolog (PTEN) protein level, while consistently downregulating Akt phosphorylation. These results indicate that Sal A negatively mediates A549 lung cancer cell line growth or apoptosis, most likely by positively regulating PTEN protein level. PMID:24648921

  16. Fibroblast Growth Factor Receptor (FGFR): A New Target for Non-small Cell Lung Cancer Therapy.

    PubMed

    Biello, Federica; Burrafato, Giovanni; Rijavec, Erika; Genova, Carlo; Barletta, Giulia; Truini, Anna; Coco, Simona; Bello, Maria Giovanna Dal; Alama, Angela; Boccardo, Francesco; Grossi, Francesco

    2016-01-01

    Lung cancer is still the leading cause of cancer related death worldwide. Fibroblast growth factor receptor (FGFR) is a tirosine-kinase receptor that is seen to be amplified or mutated in non-small cell lung cancer (NSCLC) and it plays a crucial role in tumour development and maintenance. The authors analyzed the state of the art of FGFR by reviewing the current literature. Fibroblast growth factor (FGF)-FGFR pathway and their aberrations are described, with the evaluation of their possible prognostic role in NSCLC and in particular in squamous cell carcinomas, in which FGFR is more often amplified. New therapeutic agents targeting FGFR signaling have been developed and are now in clinical evaluation. Dysregulation of FGF signaling in tumour cells is related to FGFR gene amplification or mutation, although it is still uncertain which of these aberrations represents a real predictor of response to specific inhibitors. However, recent evidence has questioned whether FGFR is a real target in squamous cell histology. The effectiveness of FGFR inhibitors is also still unclear since there are no clinical data on selected patients. Moreover, the management of specific side effects related to inhibition of the physiological role of FGF should be more thorough.

  17. Growth suppressive efficacy of human lak cells against human lung-cancer implanted into scid mice.

    PubMed

    Teraoka, S; Kyoizumi, S; Suzuki, T; Yamakido, M; Akiyama, M

    1995-06-01

    The purpose of our study was to determine the efficacy of immunotherapy using human lymphokine activated killer (LAK) cells against a human-lung squamous-cell carcinoma cell line (RERF-LC-AI) implanted into severe combined immunodeficient (SCID) mice. A statistically significant growth suppressive effect on RERF-LC-AI implanted into SCID mice was observed when human LAK cells were administered into the caudal vein of the mice treated with a continuous supply (initiated prior to LAK cells injection) of rIL-2. The human LAK cells stained with PKH 2, a fluorescent dye, for later detection using flow cytometry were administered into the caudal vein of RERF-LC-AI bearing SCID mice; the cells persisted for 7 days in the implanted lung cancer tissue and in the mouse peripheral blood, but for 5 days in the mouse spleen. The number of infiltrated human LAK cells in each tissue increased dose-dependently with the number of injected cells. The results indicate that the antitumor effect most likely occurred during the early implantation period of the human LAK cells. These results demonstrate the applicability of this model to the in vivo study of human lung cancer therapy.

  18. Effect of an epidermal growth factor receptor inhibitor in mouse models of lung cancer.

    PubMed

    Yan, Ying; Lu, Yan; Wang, Min; Vikis, Haris; Yao, Ruisheng; Wang, Yian; Lubet, Ronald A; You, Ming

    2006-12-01

    Gefitinib (Iressa, ZD1839) is a potent high-affinity competitive tyrosine kinase inhibitor aimed primarily at epidermal growth factor receptor (EGFR). Inhibitors in this class have recently been approved for clinical use in the treatment of advanced non-small cell lung cancer as monotherapy following failure of chemotherapy. We examined the efficacy of gefitinib on lung tumorigenesis in mouse models using both postinitiation and progression protocols. Gefitinib was given at a dose of 200 mg/kg body weight (i.g.) beginning either 2 or 12 weeks following carcinogen initiation. In the postinitiation protocol, gefitinib significantly inhibited both tumor multiplicity (approximately 70%) and tumor load (approximately 90%) in A/J or p53-mutant mice (P < 0.0001). Interestingly, gefitinib was also highly effective against lung carcinogenesis in the progression protocol when individual animals already have multiple preinvasive lesions in the lung. Gefitinib exhibited approximately 60% inhibition of tumor multiplicity and approximately 80% inhibition of tumor load when compared with control mice (both P < 0.0001). These data show that gefitinib is a potent chemopreventive agent in both wild-type and p53-mutant mice and that a delayed administration was still highly effective. Analyses of mutations in the EGFR and K-ras genes in lung tumors from either control or treatment groups showed no mutations in EGFR and consistent mutation in K-ras. Using an oligonucleotide array on control and gefitinib-treated lesions showed that gefitinib treatment failed to alter the activity or the expression level of EGFR. In contrast, gefitinib treatment significantly altered the expression of a series of genes involved in cell cycle, cell proliferation, cell transformation, angiogenesis, DNA synthesis, cell migration, immune responses, and apoptosis. Thus, gefitinib showed highly promising chemopreventive and chemotherapeutic activity in this mouse model of lung carcinogenesis.

  19. Radiation Therapy for Lung Cancer

    MedlinePlus

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

  20. Endophytic fungi from mangrove inhibit lung cancer cell growth and angiogenesis in vitro.

    PubMed

    Liu, Xin; Wu, Xin; Ma, Yuefan; Zhang, Wenzhang; Hu, Liang; Feng, Xiaowei; Li, Xiangyong; Tang, Xudong

    2017-03-01

    The secondary metabolites of mangrove-derived endophytic fungi contain multiple substances with novel structures and biological activities. In the present study, three types of mangrove plants, namely Kandelia candel, Rhizophora stylosa and Rhizophoraceae from Zhanjiang region including the leaves, roots and stems were collected, and endophytic fungi were isolated, purified and identified from these mangrove plants. MTT assay was used to observe the effects of the isolated endophytic fungi on the growth of A549 and NCI-H460 lung cancer cells. The effect of the endophytic fungi on lung cancer angiogenesis in vitro induced by the HPV-16 E7 oncoprotein was observed. Our results showed that 28 strains of endophytic fungi were isolated, purified and identified from the three types of mangrove plants. Ten strains of endophytic fungi significantly suppressed the growth of A549 and NCI-H460 cells. The average inhibitory rates in the A549 cells were 64.4, 59.5, 81.9, 43.9, 58.3, 56.2, 48.3, 42.4, 93.0 and 49.7%, respectively. The average inhibitory rates in the NCI-H460 cells were 41.2, 49.3, 82.7, 40.7, 53.9, 52.6, 56.8, 64.3, 91.0 and 45.6%, respectively. Particularly, three strains of endophytic fungi markedly inhibited HPV-16 E7 oncoprotein‑induced lung cancer angiogenesis in vitro. These findings contribute to the further screening of potential chemotherapeutic agents from mangrove-derived endophytic fungi.

  1. Lung cancer screening update

    PubMed Central

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

    2013-01-01

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

  2. Lung cancer prevention.

    PubMed

    Slatore, Christopher; Sockrider, Marianna

    2014-11-15

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

  3. Frondoside A Suppressive Effects on Lung Cancer Survival, Tumor Growth, Angiogenesis, Invasion, and Metastasis

    PubMed Central

    Attoub, Samir; Arafat, Kholoud; Gélaude, An; Al Sultan, Mahmood Ahmed; Bracke, Marc; Collin, Peter; Takahashi, Takashi; Adrian, Thomas E.; De Wever, Olivier

    2013-01-01

    A major challenge for oncologists and pharmacologists is to develop less toxic drugs that will improve the survival of lung cancer patients. Frondoside A is a triterpenoid glycoside isolated from the sea cucumber, Cucumaria frondosa and was shown to be a highly safe compound. We investigated the impact of Frondoside A on survival, migration and invasion in vitro, and on tumor growth, metastasis and angiogenesis in vivo alone and in combination with cisplatin. Frondoside A caused concentration-dependent reduction in viability of LNM35, A549, NCI-H460-Luc2, MDA-MB-435, MCF-7, and HepG2 over 24 hours through a caspase 3/7-dependent cell death pathway. The IC50 concentrations (producing half-maximal inhibition) at 24 h were between 1.7 and 2.5 µM of Frondoside A. In addition, Frondoside A induced a time- and concentration-dependent inhibition of cell migration, invasion and angiogenesis in vitro. Frondoside A (0.01 and 1 mg/kg/day i.p. for 25 days) significantly decreased the growth, the angiogenesis and lymph node metastasis of LNM35 tumor xenografts in athymic mice, without obvious toxic side-effects. Frondoside A (0.1–0.5 µM) also significantly prevented basal and bFGF induced angiogenesis in the CAM angiogenesis assay. Moreover, Frondoside A enhanced the inhibition of lung tumor growth induced by the chemotherapeutic agent cisplatin. These findings identify Frondoside A as a promising novel therapeutic agent for lung cancer. PMID:23308143

  4. Association between thyroid cancer and epidermal growth factor receptor mutation in female with nonsmall cell lung cancer

    PubMed Central

    Kim, Seo Yun; Kim, Hye-Ryoun; Kim, Cheol Hyeon; Koh, Jae Soo; Baek, Hee Jong; Choi, Chang-Min; Song, Joon Seon; Lee, Jae Cheol; Na, Im II

    2017-01-01

    BACKGROUND: The aim of this study was to investigate the association between epidermal growth factor receptor (EGFR) mutation and thyroid cancer in female patients with nonsmall-cell lung cancer (NSCLC). METHODS: In a retrospective study, we examined 835 female patients who were diagnosed with NSCLC and underwent an EGFR mutation test between June 2003 and August 2013. The associations of EGFR mutation with thyroid cancer and a family history of thyroid cancer were evaluated using logistic regression models. RESULTS: EGFR mutation was found in 378 of 835 patients. In addition to adenocarcinoma (P < 0.001), EGFR mutations were positively associated with a personal history of thyroid cancer (5.8% versus 2.6%; P = 0.020), while showing a trend toward inverse association with a personal history of nonthyroid cancer (5.8% vs. 9.0%; P = 0.086). Likewise, the incidence of EGFR mutations was associated with a family history of thyroid cancer (2.9% vs. 0.9%; P = 0.028), while showing a trend toward inverse association with a family history of nonthyroid cancer (27.8% vs. 33.7%; P = 0.066). Multivariate logistic regression showed that the incidence of EGFR mutations was different in women with thyroid or nonthyroid cancer (P = 0.035) and in women with a family history of thyroid or nonthyroid cancer (P = 0.023). CONCLUSIONS: Our data suggest that thyroid cancer and a family history of thyroid cancer are associated with EGFR-mutated NSCLC in female patients. The differences in the incidence of thyroid cancer and a family history of thyroid cancer by EGFR mutational status provide new insight into pathogenesis of this genetic change. PMID:28197220

  5. AAV-Mediated angiotensin 1-7 overexpression inhibits tumor growth of lung cancer in vitro and in vivo

    PubMed Central

    Mao, Yingying; Wang, Shengyao; Yan, Renhe; Bai, Na; Li, Andrew; Zhang, Yanling; Du, Hongyan; Chen, Baihong; Sumners, Colin; Li, Jinlong; Li, Hongwei

    2017-01-01

    Ang-(1-7) inhibits lung cancer cell growth both in vitro and in vivo. However, the molecular mechanism of action is unclear and also the rapid degradation of Ang-(1-7) in vivo limits its clinical application. Here, we have demonstrated that Ang- (1-7) inhibits lung cancer cell growth by interrupting pre-replicative complex assembly and restrains epithelial-mesenchymal transition via Cdc6 inhibition. Furthermore, we constructed a mutant adeno-associated viral vector AAV8 (Y733F) that produced stable and high efficient Ang-(1-7) expression in a xenograft tumor model. The results show that AAV8-mediated Ang-(1-7) over-expression can remarkably suppress tumor growth in vivo by down-regulating Cdc6 and anti-angiogenesis. Ang-(1-7) over-expression via the AAV8 method may be a promising strategy for lung cancer treatment. PMID:27861149

  6. Epidemiology of Lung Cancer

    PubMed Central

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

    2013-01-01

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

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

    PubMed Central

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

    2016-01-01

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

  8. Thoc1 inhibits cell growth via induction of cell cycle arrest and apoptosis in lung cancer cells.

    PubMed

    Wan, Jianmei; Zou, Shitao; Hu, Mengshang; Zhu, Ran; Xu, Jiaying; Jiao, Yang; Fan, Saijun

    2014-06-01

    THO complex 1 (Thoc1) is a human nuclear matrix protein that binds to the retinoblastoma tumor suppressor retinoblastoma protein (pRb). While some studies suggest that Thoc1 has characteristics of a tumor suppressor protein, whether Thoc1 can inhibit lung cancer cell growth is not clear. In the present study, we observed that Thoc1 is lowly expressed in the lung cancer cell lines SPC-A1 and NCI-H1975. Then, we investigated the potential effects of Thoc1 on lung cancer cell proliferation, cell cycle and apoptosis after stable transfection of these lines with a Thoc1 expression vector. We found that overexpression of Thoc1 can inhibit cell proliferation, induce G2/M cell cycle arrest and promote apoptosis. Further investigation indicated that overexpression of Thoc1 is involved in the inhibition of cell cycle-related proteins cyclin A1 and B1 and of pro-apoptotic factors Bax and caspase-3. In vivo experiments showed that tumors overexpressing Thoc1 display a slower growth rate than the control xenografts and show reduced expression of the protein Ki-67, which localized on the nuclear membrane. Taken together, our data show that in lung cancer cells, Thoc1 inhibits cell growth through induction of cell cycle arrest and apoptosis. These results indicate that Thoc1 may be used as a novel therapeutic target for human lung cancer treatment.

  9. Hypodiploidy, Ki-67 growth fraction and prognosis of surgically resected lung cancers.

    PubMed Central

    Pujol, J. L.; Simony, J.; Jolimoy, G.; Jaffuel, D.; Demoly, P.; Quantin, X.; Marty-Ané, C.; Boher, J. M.; Charpentier, R.; Michel, F. B.

    1996-01-01

    One hundred and thirty-seven lung cancer patients (123 non-small-cell lung cancers (NSCLC), 10 small-cell lung cancers (SCLC) and four carcinoid tumours) who underwent surgery in an attempt at complete resection were prospectively entered in a study whose aim was to determine the prognostic significance of a hypodiploidy or a multiploidy pattern of tumour cell DNA content and a high immunohistochemical reactivity of Ki-67, a nuclear antigen related to the cell cycle. Indirect immunoperoxidase reactivity of Ki-67 on frozen tumour tissue sections was evaluated both visually, using a classical semiquantitative scale, and by means of a computer-assisted image processor. Cell DNA content analysis was done using static computer-assisted cytometry on tumour cytological prints stained by the pararosaline Feulgen-Schiff technique. The ploidy was characterised for each tumour by DNA index (DI), percentage of hypodiploid cells and type of DNA content histogram (near diploid, hyperdiploid, hypodiploid and multiploid). Ki-67 immunostaining was negative in 64 tumours (48%) and positive in 69 (52%). DNA histogram classification disclosed 57 (42%) near diploid tumours. Among the 80 (58%) aneuploid tumours, 16 were hypodiploid, 44 hyperdiploid and 20 multiploid. The prevalence of both a positive Ki-67 immunostaining and an aneuploid DNA histogram differed according to histology as SCLC demonstrated a higher frequency of both features when compared with NSCLC and carcinoid tumours. On the other hand, Ki-67 immunostaining and ploidy did not significantly differ according to degree of differentiation, nodal status and Mountain's stage grouping. The percentage of cells in the hypodiploid modal DNA was significantly higher for tumours which demonstrated a high Ki-67 immunostaining, suggesting a link between growth fraction and DNA content abnormalities. In univariate analysis, survival did not differ significantly according to either the Ki-67 immunohistochemical reactivity or the DNA

  10. Lung injury and lung cancer caused by cigarette smoke-induced oxidative stress: Molecular mechanisms and therapeutic opportunities involving the ceramide-generating machinery and epidermal growth factor receptor.

    PubMed

    Goldkorn, Tzipora; Filosto, Simone; Chung, Samuel

    2014-11-20

    Chronic obstructive pulmonary disease (COPD) and lung cancer are frequently caused by tobacco smoking. However, these diseases present opposite phenotypes involving redox signaling at the cellular level. While COPD is characterized by excessive airway epithelial cell death and lung injury, lung cancer is caused by uncontrolled epithelial cell proliferation. Notably, epidemiological studies have demonstrated that lung cancer incidence is significantly higher in patients who have preexisting emphysema/lung injury. However, the molecular link and common cell signaling events underlying lung injury diseases and lung cancer are poorly understood. This review focuses on studies of molecular mechanism(s) underlying smoking-related lung injury (COPD) and lung cancer. Specifically, the role of the ceramide-generating machinery during cigarette smoke-induced oxidative stress leading to both apoptosis and proliferation of lung epithelial cells is emphasized. Over recent years, it has been established that ceramide is a sphingolipid playing a major role in lung epithelia structure/function leading to lung injury in chronic pulmonary diseases. However, new and unexpected findings draw attention to its potential role in lung development, cell proliferation, and tumorigenesis. To address this dichotomy in detail, evidence is presented regarding several protein targets, including Src, p38 mitogen-activated protein kinase, and neutral sphingomyelinase 2, the major sphingomyelinase that controls ceramide generation during oxidative stress. Furthermore, their roles are presented not only in apoptosis and lung injury but also in enhancing cell proliferation, lung cancer development, and resistance to epidermal growth factor receptor-targeted therapy for treating lung cancer.

  11. Petroleum ether extract of Chenopodium album L. prevents cell growth and induces apoptosis of human lung cancer cells

    PubMed Central

    Zhao, Ting; Pan, Hui; Feng, Yang; Li, Haizhou; Zhao, Yang

    2016-01-01

    Chenopodium album L. is a common edible herb distributed in China that has been used as a traditional Chinese medicine for antiviral, antifungal, anti-inflammatory and cancer treatment. However, to the best of our knowledge no previous reports have investigated its the function of its phytochemical extracts in lung cancer cells. The purpose of the present study was to assess the anticancer activities of the phytochemical extracts of C. album L. on human non-small cell lung cancer A549 cells. The present findings demonstrated that the petroleum ether (PE) extract of C. album L. exhibited significant growth inhibitory effects on A549 with an IC50 value of 33.31±2.79 µg/ml. As determined by MTT and colony formation assays, its growth inhibitory effects were dose- and time-dependent. Furthermore, PE extract-treated A549 cells exhibited dose-dependent cell growth arrest at the G1 phase of the cell cycle and cell apoptosis was induced. These results provide useful data on the anticancer activities of C. album L. in human lung cancer and demonstrated the novel possibilities of this plant in developing lung cancer therapies. PMID:27882153

  12. Smoking, green tea consumption, genetic polymorphisms in the insulin-like growth factors and lung cancer risk.

    PubMed

    Lin, I-Hsin; Ho, Ming-Lin; Chen, Hsuan-Yu; Lee, Hong-Shen; Huang, Chia-Chen; Chu, Yin-Hung; Lin, Shiau-Yun; Deng, Ya-Ru; He, Yu-Hao; Lien, Yu-Hui; Hsu, Chi-Wen; Wong, Ruey-Hong

    2012-01-01

    Insulin-like growth factors (IGFs) are mediators of growth hormones; they have an influence on cell proliferation and differentiation. In addition, IGF-binding protein (IGFBP)-3 could suppress the mitogenic action of IGFs. Interestingly, tea polyphenols could substantially reduce IGF1 and increase IGFBP3. In this study, we evaluated the effects of smoking, green tea consumption, as well as IGF1, IGF2, and IGFBP3 polymorphisms, on lung cancer risk. Questionnaires were administered to obtain the subjects' characteristics, including smoking habits and green tea consumption from 170 primary lung cancer cases and 340 healthy controls. Genotypes for IGF1, IGF2, and IGFBP3 were identified by polymerase chain reaction. Lung cancer cases had a higher proportion of smoking, green tea consumption of less than one cup per day, exposure to cooking fumes, and family history of lung cancer than controls. After adjusting the confounding effect, an elevated risk was observed in smokers who never drank green tea, as compared to smokers who drank green tea more than one cup per day (odds ratio (OR) = 13.16, 95% confidence interval (CI) = 2.96-58.51). Interaction between smoking and green tea consumption on lung cancer risk was also observed. Among green tea drinkers who drank more than one cup per day, IGF1 (CA)(19)/(CA)(19) and (CA)(19)/X genotypes carriers had a significantly reduced risk of lung cancer (OR = 0.06, 95% CI = 0.01-0.44) compared with IGF1 X/X carriers. Smoking-induced pulmonary carcinogenesis could be modulated by green tea consumption and their growth factor environment.

  13. Thiazolidinediones enhance vascular endothelial growth factor expression and induce cell growth inhibition in non-small-cell lung cancer cells

    PubMed Central

    2010-01-01

    Background It is known that thiazolidinediones are involved in regulating the expression of various genes, including the vascular endothelial growth factor (VEGF) gene via peroxisome proliferator-activated receptor γ (PPARγ); VEGF is a prognostic biomarker for non-small-cell lung cancer (NSCLC). Methods In this study, we investigated the effects of troglitazone and ciglitazone on the mRNA expression of VEGF and its receptors in human NSCLC cell lines, RERF-LC-AI, SK-MES-1, PC-14, and A549. These mRNA expressions were evaluated by quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR) analysis. We also studied the effect of Je-11, a VEGF inhibitor, on the growth of these cells. Results In NSCLC cells, thiazolidinediones increased the mRNA expression of VEGF and neuropilin-1, but not that of other receptors such as fms-like tyrosine kinase and kinase insert domain receptor-1. Furthermore, the PPARγ antagonist GW9662 completely reversed this thiazolidinedione-induced increase in VEGF expression. Furthermore, the addition of VEGF inhibitors into the culture medium resulted in the reversal of thiazolidinedione-induced growth inhibition. Conclusions Our results indicated that thiazolidinediones enhance VEGF and neuropilin-1 expression and induce the inhibition of cell growth. We propose the existence of a pathway for arresting cell growth that involves the interaction of thiazolidinedione-induced VEGF and neuropilin-1 in NSCLC. PMID:20214829

  14. [Lung cancer screening].

    PubMed

    Sánchez González, M

    2014-01-01

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

  15. Women and Lung Cancer

    MedlinePlus

    ... 442 Cervical Uterine Ovarian Breast Lung RESEARCH FUNDING LEVELS FISCAL YEAR 2012 (DOLLARS PER DEATH) MORE RESEARCH URGENT LY NEEDED • The biology of lung cancer is different in women • Mutations ...

  16. 1-o-acetylbritannilactone (ABL) inhibits angiogenesis and lung cancer cell growth through regulating VEGF-Src-FAK signaling

    SciTech Connect

    Zhengfu, He; Hu, Zhang; Huiwen, Miao; Zhijun, Li; Jiaojie, Zhou; Xiaoyi, Yan; Xiujun, Cai

    2015-08-21

    The search for safe, effective and affordable therapeutics against non-small cell lung cancer (NSCLC) and other lung cancers is important. Here we explored the potential effect of 1-o-acetylbritannilactone (ABL), a novel extract from Inula britannica-F, on angiogenesis and lung cancer cell growth. We demonstrated that ABL dose-dependently inhibited vascular endothelial growth factor (VEGF)-induced proliferation, migration, and capillary structure formation of cultured human umbilical vascular endothelial cells (HUVECs). In vivo, ABL administration suppressed VEGF-induced new vasculature formation in Matrigel plugs. For the mechanism investigations, we found that ABL largely inhibited VEGF-mediated activation of Src kinase and focal adhesion kinase (FAK) in HUVECs. Furthermore, treatment of A549 NSCLC cells with ABL resulted in cell growth inhibition and Src-FAK in-activation. Significantly, administration of a single dose of ABL (12 mg/kg/day) remarkably suppressed growth of A549 xenografts in nude mice. In vivo microvessels formation and Src activation were also significantly inhibited in ABL-treated xenograft tumors. Taken together, our findings suggest that ABL suppresses angiogenesis and lung cancer cell growth possibly via regulating the VEGFR-Src-FAK signaling. - Highlights: • 1-o-acetylbritannilactone (ABL) inhibits VEGF-induced angiogenesis in vivo. • ABL inhibits VEGF-induced HUVEC migration, proliferation, capillary tube formation. • ABL inhibits VEGF-mediated activation of Src and FAK in HUVECs. • ABL inhibits growth and Src-FAK activation in A549 cells. • ABL administration inhibits A549 tumor angiogenesis and growth in nude mice.

  17. Lung Cancer Indicators Recurrence

    Cancer.gov

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

  18. Exome sequencing deciphers a germline MET mutation in familial epidermal growth factor receptor-mutant lung cancer.

    PubMed

    Tode, Naoki; Kikuchi, Toshiaki; Sakakibara, Tomohiro; Hirano, Taizou; Inoue, Akira; Ohkouchi, Shinya; Tamada, Tsutomu; Okazaki, Tatsuma; Koarai, Akira; Sugiura, Hisatoshi; Niihori, Tetsuya; Aoki, Yoko; Nakayama, Keiko; Matsumoto, Kunio; Matsubara, Yoichi; Yamamoto, Masayuki; Watanabe, Akira; Nukiwa, Toshihiro; Ichinose, Masakazu

    2017-03-13

    Lung cancer accompanied by somatic activating mutations in the epidermal growth factor receptor (EGFR) gene, which is associated with a significant clinical response to the targeted therapy, is frequently found in never-smoking Asian women with adenocarcinoma. Although this implies genetic factors underlying the carcinogenesis, the etiology remains unclear. To gain insight into the pathogenic mechanisms, we sequenced the exomes in the peripheral-blood DNA from six siblings, four affected and two unaffected siblings, of a kindred with familial EGFR-mutant lung adenocarcinoma. We identified a heterozygous missense mutation in MET proto-oncogene, p.Asn375Lys, in all four affected siblings. Combined with somatic loss of heterozygosity for MET, the higher allele frequency in a Japanese sequencing database supports a causative role of the MET mutation in EGFR-mutant lung cancer. Functional assays showed that the mutation reduces the binding affinity of MET for its ligand, hepatocyte growth factor, and damages the subsequent cellular processes including proliferation, clonogenicity, motility, and tumorigenicity. The MET mutation was further observed to abrogate the ERBB3-mediated AKT signal transduction, which is shared downstream by EGFR. These findings provide an etiological view that the MET mutation is involved in the pathogenesis of EGFR-mutant lung cancer because it generates oncogenic stress that induces compensatory EGFR activation. The identification of MET in a kindred with familial EGFR-mutant lung cancer is insightful to explore the pathogenic mechanism of not only familial, but also sporadic EGFR-mutant lung cancer by underscoring MET-related signaling molecules. This article is protected by copyright. All rights reserved.

  19. Combining chemotherapy with epidermal growth factor receptor inhibition in advanced non-small cell lung cancer

    PubMed Central

    Leung, Linda; Loong, Herbert

    2012-01-01

    Treatment of advanced stage lung cancer is changing rapidly. With the new found knowledge on molecular targets such as the epidermal growth factor receptor (EGFR), effective therapy is now available in a selected population with the target mutation. Single-agent epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is a standard first-line therapy for patients with activating-EGFR mutation such as base-pair deletion in exon 19 or point mutation at exon 21. At the same time, this class of drugs may be combined with chemotherapy. Studies on the concurrent combination of chemotherapy and EGFR-TKI confirmed a lack of efficacy. A phase II study on sequential intercalated combination has demonstrated an improvement in progression-free survival (PFS), but this needs to be validated by the ongoing phase III study. The third approach is to combine EGFR-TKI as maintenance therapy after tumour response or stable disease to cytotoxic chemotherapy. Two phase III studies have shown improvement in PFS, but the use of biomarkers for the selection of maintenance therapy remains debatable. Cetuximab is a monoclonal antibody against EGFR and its combination with chemotherapy was shown to improve overall survival in an unselected population. A new biomarker using the H-score will help to select patients for this combination. PMID:22754591

  20. Aerosolised 5-azacytidine suppresses tumour growth and reprogrammes the epigenome in an orthotopic lung cancer model

    PubMed Central

    Reed, M D; Tellez, C S; Grimes, M J; Picchi, M A; Tessema, M; Cheng, Y S; March, T H; Kuehl, P J; Belinsky, S A

    2013-01-01

    Background: Epigenetic silencing by promoter methylation and chromatin remodelling affects hundreds of genes and is a causal event for lung cancer. Treatment of patients with low doses of the demethylating agent 5-azacytidine in combination with the histone deacetylase inhibitor entinostat has yielded clinical responses. The subcutaneous dosing route for consecutive days and reduced bioavailability of 5-azacytidine because of inactivation by cytidine deaminase may limit the expansion of epigenetic therapy into Phase III trials. To mitigate these barriers, an aerosol of 5-azacytidine was generated and characterised. Methods: The effect of aerosol vs systemic delivery of 5-azacytidine on tumour burden and molecular response of engrafted lung tumours in the nude rat was compared. Results: Pharmacokinetics revealed major improvement in the half-life of 5-azacytidine in lung tissue with aerosol delivery. Aerosolised 5-azacytidine significantly reduced lung tumour burden and induced global demethylation of the epigenome at one-third of the comparable effective systemic dose. High commonality for demethylation of genes was seen in tumours sampled throughout lung lobes and across treated animals receiving the aerosolised drug. Conclusion: Collectively, these findings show that aerosolised 5-azacytidine targets the lung, effectively reprogrammes the epigenome of tumours, and is a promising approach to combine with other drugs for treating lung cancer. PMID:24045660

  1. Molecular Determinants of AHPN (CD437)-Induced Growth Arrest and Apoptosis in Human Lung Cancer Cell Lines

    PubMed Central

    Li, Yin; Lin, Bingzhen; Agadir, Anissa; Liu, Ru; Dawson, Marcia I.; Reed, John C.; Fontana, Joseph A.; Bost, Frédéric; Hobbs, Peter D.; Zheng, Yun; Chen, Guo-quan; Shroot, Braham; Mercola, Dan; Zhang, Xiao-kun

    1998-01-01

    6-[3-(1-Adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (AHPN or CD437), originally identified as a retinoic acid receptor γ-selective retinoid, was previously shown to induce growth inhibition and apoptosis in human breast cancer cells. In this study, we investigated the role of AHPN/CD437 and its mechanism of action in human lung cancer cell lines. Our results demonstrated that AHPN/CD437 effectively inhibited lung cancer cell growth by inducing G0/G1 arrest and apoptosis, a process that is accompanied by rapid induction of c-Jun, nur77, and p21WAF1/CIP1. In addition, we found that expression of p53 and Bcl-2 was differentially regulated by AHPN/CD437 in different lung cancer cell lines and may play a role in regulating AHPN/CD437-induced apoptotic process. On constitutive expression of the c-JunAla(63,73) protein, a dominant-negative inhibitor of c-Jun, in A549 cells, nur77 expression and apoptosis induction by AHPN/CD437 were impaired, whereas p21WAF1/CIP1 induction and G0/G1 arrest were not affected. Furthermore, overexpression of antisense nur77 RNA in A549 and H460 lung cancer cell lines largely inhibited AHPN/CD437-induced apoptosis. Thus, expression of c-Jun and nur77 plays a critical role in AHPN/CD437-induced apoptosis. Together, our results reveal a novel pathway for retinoid-induced apoptosis and suggest that AHPN/CD437 or analogs may have a better therapeutic efficacy against lung cancer. PMID:9671482

  2. Immunotherapy for lung cancer.

    PubMed

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

    2016-07-01

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

  3. Monocyte to macrophage differentiation-associated (MMD) targeted by miR-140-5p regulates tumor growth in non-small cell lung cancer

    SciTech Connect

    Li, Weina; He, Fei

    2014-07-18

    Highlights: • Expression of MMD is increased in lung cancer tissues. • Knockdown of MMD inhibits growth of A549 and LLC cells in vitro and in vivo. • MMD is a direct functional target of miR-140-5p. • MiR-140-5p/MMD axis regulates Erk1/2 signaling. - Abstract: Monocyte to macrophage differentiation-associated (MMD) is identified in macrophages as a gene associated with the differentiation from monocytes to macrophages. Recent microarray analysis for non-small cell lung cancer (NSCLC) suggests that MMD is an important signature associated with relapse and survival among patients with NSCLC. Therefore, we speculate that MMD likely plays a role in lung cancer. In this study, we found that the protein level of MMD was increased in lung cancer compared to benign lung tissues, and knockdown of MMD inhibited the growth of A549 and Lewis lung cancer cells (LLC) in vitro and in vivo. Integrated analysis demonstrated that MMD was a direct functional target of miR-140-5p. Furthermore, we found that miR-140-5p/MMD axis could affect the cell proliferation of lung cancer cells by regulating Erk signaling. Together, our results highlight the significance of miR-140-5p/MMD axis in lung cancer, and miR-140-5p/MMD axis could serve as new molecular targets for the therapy against lung cancer.

  4. Lung cancer in women

    PubMed Central

    Barrera-Rodriguez, Raúl; Morales-Fuentes, Jorge

    2012-01-01

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

  5. Lung Cancer Prevention

    MedlinePlus

    ... following substances increases the risk of lung cancer: Asbestos . Arsenic . Chromium. Nickel. Beryllium. Cadmium . Tar and soot. ... being exposed to cancer-causing substances, such as asbestos, arsenic, nickel, and chromium, may help lower their ...

  6. Transforming Growth Factor-β-Induced RBFOX3 Inhibition Promotes Epithelial-Mesenchymal Transition of Lung Cancer Cells

    PubMed Central

    Kim, Yong-Eun; Kim, Jong Ok; Park, Ki-Sun; Won, Minho; Kim, Kyoon Eon; Kim, Kee K.

    2016-01-01

    The RNA-binding protein Rbfox3 is a well-known splicing regulator that is used as a marker for post-mitotic neurons in various vertebrate species. Although recent studies indicate a variable expression of Rbfox3 in non-neuronal tissues, including lung tissue, its cellular function in lung cancer remains largely unknown. Here, we report that the number of RBFOX3-positive cells in tumorous lung tissue is lower than that in normal lung tissue. As the transforming growth factor-β (TGF-β) signaling pathway is important in cancer progression, we investigated its role in RBFOX3 expression in A549 lung adenocarcinoma cells. TGF-β1 treatment inhibited RBFOX3 expression at the transcriptional level. Further, RBFOX3 depletion led to a change in the expression levels of a subset of proteins related to epithelial-mesenchymal transition (EMT), such as E-cadherin and Claudin-1, during TGF-β1-induced EMT. In immunofluorescence microscopic analysis, mesenchymal morphology was more prominent in RBFOX3-depleted cells than in control cells. These findings show that TGF-β-induced RBFOX3 inhibition plays an important role in EMT and propose a novel role for RBFOX3 in cancer progression. PMID:27432190

  7. miR-1207-5p suppresses lung cancer growth and metastasis by targeting CSF1

    PubMed Central

    Fan, Songqing; Wen, Qiuyuan; Lu, Yuanjun; Wang, Jia; Zhang, Xuemei; Wei, Lingyu; He, Wei; Ye, Qiurong; Yan, Qun; Li, Guiyuan; Ma, Jian

    2016-01-01

    We previously reported that miR-1207-5p can inhibit epithelial-mesenchymal transition (EMT) induced by growth factors such as EGF and TGF-β, but the exact mechanism is unclear. Here we identified that Colony stimulating factor 1 (CSF1) is a target gene of miR-1207-5p. CSF1 controls the production, differentiation and function of macrophage and promotes the release of proinflammatory chemokines. We showed that miR-1207-5p inhibited lung cancer cell A549 proliferation, migration and invasion in vitro, and suppressed the STAT3 and AKT signalings. miR-1207-5p overexpression can increase HUVEC angiogenesis, and can modulate the M2 phenotype of macrophage. miR-1207-5p also significantly inhibited A549 cells metastasis in a nude mouse xenograft model. miR-1207-5p and CSF1 expression levels and their relationship with lung cancer survival and metastasis status were assayed by means of a lung cancer tissue microarray. Macrophage is an essential part of the tumor microenvironment, thus the miR-1207-5p-CSF1 axis maybe a new regulator of lung cancer development through modulating the tumor microenvironment. PMID:27107415

  8. Splenectomy inhibits non-small cell lung cancer growth by modulating anti-tumor adaptive and innate immune response.

    PubMed

    Levy, Liran; Mishalian, Inbal; Bayuch, Rachel; Zolotarov, Lida; Michaeli, Janna; Fridlender, Zvi G

    2015-04-01

    It has been shown that inhibitors of the immune system reside in the spleen and inhibit the endogenous antitumor effects of the immune system. We hypothesized that splenectomy would inhibit the growth of relatively large non-small lung cancer (NSCLC) tumors by modulating the systemic inhibition of the immune system, and in particular Myeloid Derived Suppressor Cells (MDSC). The effect of splenectomy was evaluated in several murine lung cancer models. We found that splenectomy reduces tumor growth and the development of lung metastases, but only in advanced tumors. In immune-deficient NOD-SCID mice the effect of splenectomy on tumor growth and metastatic spread disappeared. Splenectomy significantly reduced the presence of MDSC, and especially monocytic-MDSC in the circulation and inside the tumor. Specific reduction of the CCR2+ subset of monocytic MDSC was demonstrated, and the importance of the CCL2-CCR2 axis was further shown by a marked reduction in CCL2 following splenectomy. These changes were followed by changes in the macrophages contents of the tumors to become more antitumorigenic, and by increased activation of CD8(+) Cytotoxic T-cells (CTL). By MDSC depletion, and adoptive transfer of MDSCs, we demonstrated that the effect of splenectomy on tumor growth was substantially mediated by MDSC cells. We conclude that the spleen is an important contributor to tumor growth and metastases, and that splenectomy can blunt this effect by depletion of MDSC, changing the amount and characteristics of myeloid cells and enhancing activation of CTL.

  9. Addressing epidermal growth factor receptor tyrosine kinase inhibitor resistance in non-small cell lung cancer.

    PubMed

    Noda, Shoko; Kanda, Shintaro

    2016-01-01

    Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have significantly improved the survival of patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR activating mutations. However, nearly all EGFR-mutant NSCLC tumors eventually acquire resistance to the currently used EGFR-TKIs and subsequently progress clinically. Acquired resistance to EGFR-TKIs is thus a huge issue in the treatment of EGFR-mutant NSCLC at present. On one hand, T790M second-site mutation has been recognized as a key mechanism of EGFR-TKI resistance, and third generation EGFR-TKIs such as osimertinib and rociletinib have been developed to overcome tumor cells harboring the T790M mutation. On the other hand, combination with cytotoxic chemotherapy is also expected as another strategy for preventing the acquired resistance to current EGFR-TKIs and prolonging the survival benefits by EGFR-TKIs. Here, we review updated strategies for preventing or overcoming acquired resistance to EGFR-TKIs.

  10. Genetic profiling and epidermal growth factor receptor-directed therapy in nonsmall cell lung cancer.

    PubMed

    Cadranel, J; Zalcman, G; Sequist, L

    2011-01-01

    The principle of preferentially selecting patients most likely to benefit from therapy according to their genetic profile has led to substantial clinical benefit in some tumour types, and has potential to considerably refine treatment in advanced nonsmall cell lung cancer (NSCLC). Effective, reliable use of molecular biomarkers to inform clinical practice requires the standardisation of testing methods and careful assessment of biomarkers' predictive and prognostic value. Although a number of studies have shown that patients with activating mutations in exons 18-21 of the epidermal growth factor receptor (EGFR) gene respond particularly well to gefitinib and erlotinib, a prospective, randomised study was needed to differentiate between the prognostic and predictive value of EGFR mutations. From one such study, it appeared that mutational testing should become standard at diagnosis, at least for adenocarcinoma patients with a never or low smoking history, as clinical predictors are insufficient to optimise treatment. However, outstanding questions remain: what are the treatment options for patients with tumours resistant to erlotinib/gefitinib? What conclusions about treatment can we draw from EGFR copy number or KRAS mutation status? What role should anti-EGFR antibodies play in NSCLC treatment, and in which patients? This review considers current evidence linking biomarker profile to efficacy of EGFR-targeted therapy in NSCLC, and clinical implications of recent findings.

  11. Immunotherapy in Lung Cancer.

    PubMed

    Castellanos, Emily H; Horn, Leora

    2016-01-01

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

  12. Role of Insulin-Like Growth Factor-1 Signaling Pathway in Cisplatin-Resistant Lung Cancer Cells

    SciTech Connect

    Sun Yunguang; Zheng Siyuan; Torossian, Artour; Speirs, Christina K.; Schleicher, Stephen; Giacalone, Nicholas J.; Carbone, David P.; Zhao Zhongming; Lu Bo

    2012-03-01

    Purpose: The development of drug-resistant phenotypes has been a major obstacle to cisplatin use in non-small-cell lung cancer. We aimed to identify some of the molecular mechanisms that underlie cisplatin resistance using microarray expression analysis. Methods and Materials: H460 cells were treated with cisplatin. The differences between cisplatin-resistant lung cancer cells and parental H460 cells were studied using Western blot, MTS, and clonogenic assays, in vivo tumor implantation, and microarray analysis. The cisplatin-R cells were treated with human recombinant insulin-like growth factor (IGF) binding protein-3 and siRNA targeting IGF-1 receptor. Results: Cisplatin-R cells illustrated greater expression of the markers CD133 and aldehyde dehydrogenase, more rapid in vivo tumor growth, more resistance to cisplatin- and etoposide-induced apoptosis, and greater survival after treatment with cisplatin or radiation than the parental H460 cells. Also, cisplatin-R demonstrated decreased expression of insulin-like growth factor binding protein-3 and increased activation of IGF-1 receptor signaling compared with parental H460 cells in the presence of IGF-1. Human recombinant IGF binding protein-3 reversed cisplatin resistance in cisplatin-R cells and targeting of IGF-1 receptor using siRNA resulted in sensitization of cisplatin-R-cells to cisplatin and radiation. Conclusions: The IGF-1 signaling pathway contributes to cisplatin-R to cisplatin and radiation. Thus, this pathway represents a potential target for improved lung cancer response to treatment.

  13. Occupational lung cancer

    SciTech Connect

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

    1992-06-01

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

  14. A novel long noncoding RNA AK001796 acts as an oncogene and is involved in cell growth inhibition by resveratrol in lung cancer

    SciTech Connect

    Yang, Qiaoyuan; Xu, Enwu; Dai, Jiabin; Liu, Binbin; Han, Zhiyuan; Wu, Jianjun; Zhang, Shaozhu; Peng, Baoying; Zhang, Yajie; Jiang, Yiguo

    2015-06-01

    Lung cancer is the most common form of cancer throughout the world. The specific targeting of long noncoding RNAs (lncRNAs) by resveratrol opened a new avenue for cancer chemoprevention. In this study, we found that 21 lncRNAs were upregulated and 19 lncRNAs were downregulated in lung cancer A549 cells with 25 μmol/L resveratrol treatment determined by microarray analysis. AK001796, the lncRNA with the most clearly altered expression, was overexpressed in lung cancer tissues and cell lines, but its expression was downregulated in resveratrol-treated lung cancer cells. By monitoring cell proliferation and growth in vitro and tumor growth in vivo, we observed a significant reduction in cell viability in lung cancer cells and a slow growth in the tumorigenesis following AK001796 knockdown. We also found that AK001796 knockdown caused a cell-cycle arrest, with significant increases in the percentage of cells in G{sub 0}/G{sub 1} in lung cancer cells. By using cell cycle pathway-specific PCR arrays, we detected changes in a number of cell cycle-related genes related to lncRNA AK001796 knockdown. We further investigated whether AK001796 participated in the anticancer effect of resveratrol and the results showed that reduced lncRNA AK001796 level potentially impaired the inhibitory effect of resveratrol on cell proliferation. To our knowledge, this is the first study to report the changes in an lncRNA expression profile induced by resveratrol in lung cancer. - Highlights: • LncRNA AK001796 played an oncogenic role in lung carcinogenesis. • LncRNA AK001796 was downregulated in resveratrol-treated lung cancer cells. • LncRNA AK001796 was involved in the inhibition of cell growth by resveratrol.

  15. Inhibition of Calcium-Activated Chloride Channel ANO1/TMEM16A Suppresses Tumor Growth and Invasion in Human Lung Cancer

    PubMed Central

    Jia, Linghan; Liu, Wen; Guan, Lizhao; Lu, Min; Wang, KeWei

    2015-01-01

    Lung cancer or pulmonary carcinoma is primarily derived from epithelial cells that are thin and line on the alveolar surfaces of the lung for gas exchange. ANO1/TMEM16A, initially identified from airway epithelial cells, is a member of Ca2+-activated Cl- channels (CaCCs) that function to regulate epithelial secretion and cell volume for maintenance of ion and tissue homeostasis. ANO1/TMEM16A has recently been shown to be highly expressed in several epithelium originated carcinomas. However, the role of ANO1 in lung cancer remains unknown. In this study, we show that inhibition of calcium-activated chloride channel ANO1/TMEM16A suppresses tumor growth and invasion in human lung cancer. ANO1 is upregulated in different human lung cancer cell lines. Knocking-down ANO1 by small hairpin RNAs inhibited proliferation, migration and invasion of GLC82 and NCI-H520 cancel cells evaluated by CCK-8, would-healing, transwell and 3D soft agar assays. ANO1 protein is overexpressed in 77.3% cases of human lung adenocarcinoma tissues detected by immunohistochemistry. Furthermore, the tumor growth in nude mice implanted with GLC82 cells was significantly suppressed by ANO1 silencing. Taken together, our findings provide evidence that ANO1 overexpression contributes to tumor growth and invasion of lung cancer; and suppressing ANO1 overexpression may have therapeutic potential in lung cancer therapy. PMID:26305547

  16. Inhibition of Calcium-Activated Chloride Channel ANO1/TMEM16A Suppresses Tumor Growth and Invasion in Human Lung Cancer.

    PubMed

    Jia, Linghan; Liu, Wen; Guan, Lizhao; Lu, Min; Wang, KeWei

    2015-01-01

    Lung cancer or pulmonary carcinoma is primarily derived from epithelial cells that are thin and line on the alveolar surfaces of the lung for gas exchange. ANO1/TMEM16A, initially identified from airway epithelial cells, is a member of Ca2+-activated Cl- channels (CaCCs) that function to regulate epithelial secretion and cell volume for maintenance of ion and tissue homeostasis. ANO1/TMEM16A has recently been shown to be highly expressed in several epithelium originated carcinomas. However, the role of ANO1 in lung cancer remains unknown. In this study, we show that inhibition of calcium-activated chloride channel ANO1/TMEM16A suppresses tumor growth and invasion in human lung cancer. ANO1 is upregulated in different human lung cancer cell lines. Knocking-down ANO1 by small hairpin RNAs inhibited proliferation, migration and invasion of GLC82 and NCI-H520 cancel cells evaluated by CCK-8, would-healing, transwell and 3D soft agar assays. ANO1 protein is overexpressed in 77.3% cases of human lung adenocarcinoma tissues detected by immunohistochemistry. Furthermore, the tumor growth in nude mice implanted with GLC82 cells was significantly suppressed by ANO1 silencing. Taken together, our findings provide evidence that ANO1 overexpression contributes to tumor growth and invasion of lung cancer; and suppressing ANO1 overexpression may have therapeutic potential in lung cancer therapy.

  17. Crosstalk with cancer-associated fibroblasts induces resistance of non-small cell lung cancer cells to epidermal growth factor receptor tyrosine kinase inhibition

    PubMed Central

    Choe, Chungyoul; Shin, Yong-Sung; Kim, Changhoon; Choi, So-Jung; Lee, Jinseon; Kim, So Young; Cho, Yong Beom; Kim, Jhingook

    2015-01-01

    Although lung cancers with activating mutations in the epidermal growth factor receptor (EGFR) are highly sensitive to selective EGFR tyrosine kinase inhibitors (TKIs), these tumors invariably develop acquired drug resistance. Host stromal cells have been found to have a considerable effect on the sensitivity of cancer cells to EGFR TKIs. Little is known, however, about the signaling mechanisms through which stromal cells contribute to the response to EGFR TKI in non-small cell lung cancer. This work examined the role of hedgehog signaling in cancer-associated fibroblast (CAF)-mediated resistance of lung cancer cells to the EGFR TKI erlotinib. PC9 cells, non-small cell lung cancer cells with EGFR-activating mutations, became resistant to the EGFR TKI erlotinib when cocultured in vitro with CAFs. Polymerase chain reaction and immunocytochemical assays showed that CAFs induced epithelial to mesenchymal transition phenotype in PC9 cells, with an associated change in the expression of epithelial to mesenchymal transition marker proteins including vimentin. Importantly, CAFs induce upregulation of the 7-transmembrane protein smoothened, the central signal transducer of hedgehog, suggesting that the hedgehog signaling pathway is active in CAF-mediated drug resistance. Indeed, downregulation of smoothened activity with the smoothened antagonist cyclopamine induces remodeling of the actin cytoskeleton independently of Gli-mediated transcriptional activity in PC9 cells. These findings indicate that crosstalk with CAFs plays a critical role in resistance of lung cancer to EGFR TKIs through induction of the epithelial to mesenchymal transition and may be an ideal therapeutic target in lung cancer. PMID:26676152

  18. Familial risk for lung cancer

    PubMed Central

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

    2017-01-01

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

  19. Lung cancer screening.

    PubMed

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

    2015-01-01

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

  20. Growth suppression by MYC inhibition in small cell lung cancer cells with TP53 and RB1 inactivation

    PubMed Central

    Fiorentino, Francesco Paolo; Tokgün, Elvan; Solé-Sánchez, Sònia; Giampaolo, Sabrina; Tokgün, Onur; Jauset, Toni; Kohno, Takashi; Perucho, Manuel; Soucek, Laura; Yokota, Jun

    2016-01-01

    Small cell lung cancer (SCLC) is the most aggressive type of lung cancer with high mortality. One of the MYC family genes, MYC, MYCL or MYCN, is amplified in ~20% of the SCLCs; therefore, MYC proteins are potential therapeutic targets in SCLC patients. We investigated the therapeutic impact of Omomyc, a MYC dominant negative, in a panel of SCLC cell lines. Strikingly, Omomyc suppressed the growth of all tested cell lines by inducing cell cycle arrest and/or apoptosis. Induction of G1 arrest by Omomyc was found to be dependent on the activation of CDKN1A, in part, through the TP73 pathway. Our results strongly indicate that SCLC cells carrying amplification of MYC, MYCL or MYCN are addicted to MYC function, suggesting that MYC targeting would be an efficient therapeutic option for SCLC patients. PMID:27105536

  1. Cyclooxygenase-2 modulates the insulin-like growth factor axis in non-small-cell lung cancer.

    PubMed

    Põld, Mehis; Krysan, Kostyantyn; Põld, Anu; Dohadwala, Mariam; Heuze-Vourc'h, Nathalie; Mao, Jenny T; Riedl, Karen L; Sharma, Sherven; Dubinett, Steven M

    2004-09-15

    Constitutive overexpression of cyclooxygenase-2 (COX-2) occurs frequently in several different malignancies, including lung, colon, breast, and prostate cancer. Clinical studies have established elevated serum insulin-like growth factor (IGF-I) content and IGF-I:IGF-binding protein 3 (IGFBP-3) ratio as risk factors for these same malignancies. Therefore, we sought to determine the link between COX-2 expression and the IGF axis in COX-2 gene-modified human non-small-cell lung cancer (NSCLC) cells. Overexpression of COX-2 in NSCLC cells enhanced the antiapoptotic and mitogenic effects of IGF-I and IGF-II, facilitated the autophosphorylation of the type 1 IGF receptor, increased class IA phosphatidylinositol 3'-kinase activity, and decreased expression of IGFBP-3. Thus, these findings show that COX-2 augments the stimulatory arm of the IGF axis.

  2. Three generations of epidermal growth factor receptor tyrosine kinase inhibitors developed to revolutionize the therapy of lung cancer

    PubMed Central

    Zhang, Haijun

    2016-01-01

    Lung cancer, ~80%–85% of which is non-small-cell lung cancer (NSCLC), is the leading cause of cancer-related mortality worldwide. Sensitizing mutations in epidermal growth factor receptor (EGFR) gene (EGFRm+), such as exon 19 deletions and exon 21 L858R point mutations, are the most important drivers in NSCLC patients. In this respect, small-molecule EGFR tyrosine kinase inhibitors (TKIs) have been designed and developed, which launched the era of targeted, personalized and precise medicine for lung cancer. Patients with EGFRm+ could achieve good responses to the treatment with the first-generation EGFR TKIs, such as erlotinib and gefitinib. However, most patients develop acquired drug resistance mostly driven by the T790M mutation occurring within exon 20. Although the second-generation EGFR TKIs, such as afatinib, dacomitinib and neratinib, demonstrated promising activity against T790M in preclinical models, they have failed to overcome resistance in patients due to dose-limiting toxicity. Recently, the third-generation EGFR TKIs have shown to be effective against cell lines and murine models harboring T790M mutations while sparing wild-type EGFR, which represents a promising breakthrough approach in overcoming T790M-mediated resistance in NSCLC patients. This article provides a comprehensive review of the therapy revolution for NSCLC with three generations of EGFR TKIs. PMID:27920501

  3. Lung Cancer Biomarkers.

    PubMed

    I, Hoseok; Cho, Je-Yoel

    2015-01-01

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

  4. Lung Cancer Screening Update.

    PubMed

    Ruchalski, Kathleen L; Brown, Kathleen

    2016-07-01

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

  5. Genetics Home Reference: lung cancer

    MedlinePlus

    ... present in up to half of all lung cancer cases. These genes each provide instructions for making a protein that is embedded within the cell membrane. When these proteins are turned on (activated) by binding to other molecules, signaling pathways are triggered within cells that promote cell growth ...

  6. Lycopene and Lung Cancer

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  7. Lung Cancer: Glossary

    MedlinePlus

    ... another type of non-small cell lung cancer Larynx: The voice box; located above the windpipe Limited ... allows for the passage of air from the larynx to the bronchial tubes Transfusion: The infusion of ...

  8. Lung Cancer Rates by State

    MedlinePlus

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

  9. Expression profile, clinical significance, and biological function of insulin-like growth factor 2 messenger RNA-binding proteins in non-small cell lung cancer.

    PubMed

    Shi, Run; Yu, Xinnian; Wang, Yajing; Sun, Jing; Sun, Qi; Xia, Wenjie; Dong, Gaochao; Wang, Anpeng; Gao, Zhaojia; Jiang, Feng; Xu, Lin

    2017-04-01

    Insulin-like growth factor 2 messenger RNA-binding proteins have been described to associate with malignant process in many cancers. However, the role of insulin-like growth factor 2 messenger RNA-binding protein family has not been thoroughly elucidated in non-small cell lung cancer. This study was to investigate the expression profile, clinical significance, and biological function of insulin-like growth factor 2 messenger RNA-binding proteins family in non-small cell lung cancer. The expression levels of IGF2BP1-IGF2BP3 in tumor and adjacent normal tissues were determined, and association with clinicopathological features and overall survival was investigated by analyzing The Cancer Genome Atlas lung cancer database. Proliferation, migration, invasion assays, and flow-cytometry analysis were used to investigate the biological function in vitro. Insulin-like growth factor 2 messenger RNA-binding protein expression levels were significantly increased in non-small cell lung cancer compared to adjacent normal lung tissues. Chi-square test indicated that IGF2BP1 and IGF2BP3 expressions correlated with some meaningful clinical characteristics in non-small cell lung cancer. Kaplan-Meier analysis showed that high-level expression of IGF2BP1 or IGF2BP3 predicted poor overall survival in lung adenocarcinoma patients. Multivariate regression analysis showed that high level of IGF2BP3 was an independent risk factor for poor prognosis in lung adenocarcinoma patients (hazard ratio = 1.616, p = 0.017). In vitro, knockdown of IGF2BP3 inhibited lung adenocarcinoma cell proliferation by inducing cell cycle arrest and apoptosis, and undermined abilities of migration and invasion, and overexpression of IGF2BP3 could promote malignant phenotypes in lung adenocarcinoma cells. Our study revealed that expression of insulin-like growth factor 2 messenger RNA-binding proteins was widely upregulated and correlated with some certain clinicopathological features in non-small cell

  10. Study of lung-metastasized prostate cancer cell line chemotaxis to epidermal growth factor with a BIOMEMS device

    NASA Astrophysics Data System (ADS)

    Tata, Uday; Rao, Smitha M. N.; Sharma, Akash; Pabba, Krishna; Pokhrel, Kushal; Adhikari, Bandita; Lin, Victor K.; Chiao, J.-C.

    2012-09-01

    Understanding the effects of different growth factors on cancer metastasis will enable researchers to develop effective post-surgery therapeutic strategies to stop the spread of cancer. Conventional Boyden chamber assays to evaluate cell motility in metastasis studies require high volumes of reagents and are impractical for high-throughput analysis. A microfluidic device was designed for arrayed assaying of prostate cancer cell migration towards different growth factors. The device was created with polydimethylsiloxane (PDMS) and featured two wells connected by 10 micro channels. One well was for cell seeding and the other well for specific growth factors. Each channel has a width of 20 μm, a length of 1 mm and a depth of 10 μm. The device was placed on a culture dish and primed with growth media. Lung-metastasized cells in suspension of RPMI 1640 media1 supplemented with 2% of fetal bovine serum (FBS) were seeded in the cell wells. Cell culture media with epidermal growth factor (EGF) of 25, 50, 75, 100 and 125 ng ml-1 concentrations were individually added in the respective growth factor wells. A 5-day time-lapsed study of cell migration towards the chemoattractant was performed. The average numbers of cells per device in the microchannels were obtained for each attractant condition. The results indicated migration of cells increased from 50 to 100 ng ml-1 of EGF and significantly decreased at 125 ng ml-1 of EGF, as compared to control.

  11. Targeted therapy in non-small cell lung cancer: a focus on epidermal growth factor receptor mutations.

    PubMed

    Milano, Gérard A

    2015-12-01

    The main molecular targeting of lung cancer [non-small cell lung cancer (NSCLC)] concerns mutations of epidermal growth factor receptor (EGFR). The awaited responsiveness of tumors carrying these mutations is high with for instance 60% to 80% with tyrosine kinase inhibitors hitting EGFR mutations. The EGFR T790M as a secondary mutation is responsible for the occurrence of a resistance phenomenon. A multitude of drugs have been produced and tested with the property of a specific binding at the EGFR T790M site. There is currently an evolution oriented to a robust genotyping methods allowing the identification of given molecular anomalies (pyrosequencing for instance) towards the consideration of a much larger set of molecular anomalies under the form of a global genotyping realized with the use of next-generation sequencing (NGS). This phase of whole genome analysis necessitates the introduction of a specialized staff for data treatment. A possible substitution plasma/tumor for the mutation analyses is perceptible in lung cancer, a preference being however given to the intratumoral direct investigation when this is feasible. EGFR mutations as targetable anomalies are illustrative examples, that the management of NSCLC is currently drawing a significant benefit from personalized therapy.

  12. Recent advances in lung cancer biology

    SciTech Connect

    Lechner, J.

    1995-12-31

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

  13. Integrin β3 and CD44 levels determine the effects of the OPN-a splicing variant on lung cancer cell growth

    PubMed Central

    Sheu, Gwo-Tarng; Chang, Hui-Yi; Chen, Mei-Yu; Lin, Yu-Ying; Chuang, Cheng-Yen; Hsu, Shih-Lan; Chang, Jinghua Tsai

    2016-01-01

    Osteopontin (OPN), a phosphorylated glycoprotein, is frequently overexpressed in cancer. Among the three OPN isoforms, OPN-a is the most highly expressed in lung cancer cell lines and lung tumors. Overexpression of OPN-a greatly reduced CL1-5 lung adenocarcinoma cell growth, but had no effect on growth in A549 lung adenocarcinoma cells. Examination of the expression of integrins and CD44, which are possible OPN-a receptors, revealed that differences in integrin β3 levels might explain this discrepancy between CL1-5 and A549 cells. When integrin β3 was ectopically expressed in A549 cells, OPN-a inhibited their growth, whereas OPN-a increased cell growth following integrin β3 knockdown in CL1-5 cells. This OPN-a-induced increase in growth appeared to result from activation of the CD44/NFκB pathway. Our results demonstrated that OPN-a inhibits growth of cells with high integrin β3 levels and increases growth via activation of the CD44/NFκB pathway in cells with low integrin β3 levels. Thus, OPN-a, integrin β3, and CD44 interact to affect lung cancer cell growth, and this study may aid in the development of cancer treatment strategies involving these molecules. PMID:27487131

  14. Expression of Sonic Hedgehog (SHH) in human lung cancer and the impact of YangZheng XiaoJi on SHH-mediated biological function of lung cancer cells and tumor growth.

    PubMed

    Jiang, Wen G; Ye, Lin; Ruge, Fiona; Sun, Ping-Hui; Sanders, Andrew J; Ji, Ki; Lane, Jane; Zhang, Lijian; Satherley, Lucy; Weeks, Hoi P; Zhi, Xiuyi; Gao, Yong; Wei, Cong; Wu, Yiling; Mason, Malcolm D

    2015-03-01

    Sonic Hedgehog (SHH) is a protein that is aberrantly expressed in various human tumors. SHH and its signaling molecules have been indicated as potential therapeutic targets. In the present study, we evaluated the expression of SHH transcript in human non-small cell lung cancer (NSCLC) tissues and investigated the impact of inhibiting SHH together with a traditional Chinese medicine formula, YangZheng XiaoJi (YZXJ), on the function and growth of lung cancer cells. Human NSCLC tissues had significantly higher levels of the SHH transcript compared matched normal lung tissues (n=83). TNM2 tumors and tumors with pleural invasion had higher levels than TNM1 and non-invasive tumors. High SHH levels were associated with a shorter overall survival (OS) of the patients. A SHH inhibitor, cyclopamine, and YZXJ alone or in combination had a marked inhibitory effect on cellular invasion and cellular migration of human lung cancer cells, A549 and SKMES1. YangZheng XiaoJi and its combination with cyclopamine also significantly reduced the growth of lung tumors in vivo together with a reduction of SHH and smoothened (Smo) proteins in the lung tumors. The present study provides evidence that blocking SHH by way of small inhibitor and by YangZheng XiaoJi has a profound influence on lung cancer cells as seen by in vitro invasion and cell migration and in vivo tumor growth. Together with the aberrant expression of SHH in NSCLC tumors in the patients, it is suggested that SHH is a potential target for therapies for NSCLC.

  15. 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 ...

  16. IL-6 promotes growth and epithelial-mesenchymal transition of CD133+ cells of non-small cell lung cancer.

    PubMed

    Lee, Soo Ok; Yang, Xiaodong; Duan, Shanzhou; Tsai, Ying; Strojny, Laura R; Keng, Peter; Chen, Yuhchyau

    2016-02-09

    We examined IL-6 effects on growth, epithelial-mesenchymal transition (EMT) process, and metastatic ability of CD133+ and CD133- cell subpopulations isolated from three non-small cell lung cancer (NSCLC) cell lines: A549, H157, and H1299. We developed IL-6 knocked-down and scramble (sc) control cells of A549 and H157 cell lines by lentiviral infection system, isolated CD133+ and CD133- sub-populations, and investigated the IL-6 role in self-renewal/growth of these cells. IL-6 showed either an inhibitory or lack of effect in modulating growth of CD133- cells depending on intracellular IL-6 levels, but there was higher self-renewal ability of IL-6 expressing CD133+ cells than IL-6 knocked down cells, confirming the promoter role of IL-6 in CD133+ cells growth. We then examined tumor growth of xenografts developed from CD133+ cells of A549IL-6si vs. A549sc cell lines. Consistently, there was retarded growth of tumors developed from A549IL-6si, CD133+ cells compared to tumors originating from A549sc, CD133+ cells. The effect of IL-6 in promoting CD133+ self-renewal was due to hedgehog (Hhg) and Erk signaling pathway activation and higher Bcl-2/Bcl-xL expression. We also investigated whether IL-6 regulates the EMT process of CD133- and CD133+ cells differently. Expression of the EMT/metastasis-associated molecules in IL-6 expressing cells was higher than in IL-6 knocked down cells. Together, we demonstrated dual roles of IL-6 in regulating growth of CD133- and CD133+ subpopulations of lung cancer cells and significant regulation of IL-6 on EMT/metastasis increase in CD133+ cells, not in CD133- cells.

  17. Tetramethylpyrazine inhibits tumor growth of lung cancer through disrupting angiogenesis via BMP/Smad/Id-1 signaling.

    PubMed

    Jia, Youchao; Wang, Zhigang; Zang, Aimin; Jiao, Shunchang; Chen, Sumei; Fu, Yan

    2016-05-01

    The underlying mechanisms of inhibitory effects induced by tetramethylpyrazine (TMP) on angiogenesis and tumor growth of lung cancer were investigated. In vitro cell proliferation, migration, and tube formation of human microvascular endothelial cells (HMEC-1) were evaluated by a 3-(4,5-dimethylthiazol-2-yl)-2,5-dephenyltetrazolium bromide (MTT), wound healing, Transwell, and Matrigel assays. The expression of BMP/Smad/Id-1 signals was detected by RT-PCR and western blotting. In an A549 xenograft tumor model, TMP (40 and 80 mg/kg/day) was intraperitoneally injected into mice. The expressions of CD31, phosphorylated Smad1/5/8, and Id-1 were measured by immunohistochemistry. We demonstrated that TMP inhibited proliferation, migration, and capillary tube formation of HMEC-1 in a dose- and time-dependent manner. Furthermore, treatment of HMEC-1 cells with TMP (0.4 mg/ml) significantly upregulated BMP2 expression and downregulated BMPRIA, BMPRII, phosphorylated Smad1/5/8, and Id-1 expression. In addition, administrations of TMP remarkably inhibited tumor growth of A549 xenograft in nude mice. The CD31, phosphorylated Smad1/5/8, and Id-1 expression were significantly inhibited in TMP-treated xenograft tumors compared with the vehicle. In conclusion, our results indicated that TMP suppressed angiogenesis and tumor growth of lung cancer via blocking the BMP/Smad/Id-1 signaling.

  18. GZD856, a novel potent PDGFRα/β inhibitor, suppresses the growth and migration of lung cancer cells in vitro and in vivo.

    PubMed

    Zhang, Zhang; Ren, Xiaomei; Lu, Xiaoyun; Wang, Deping; Hu, Xianjing; Zheng, Yi; Song, Liyan; Pang, Hongwen; Yu, Rongmin; Ding, Ke

    2016-05-28

    Platelet-derived growth factor receptors (PDGFRα/β) play critical roles in the autocrine-stimulated growth and recruitment of cancer-associated fibroblasts (CAFs) of human lung cancer cells. We have identified GZD856 as a new PDGFR inhibitor that potently inhibits PDGFRα/β kinase activity and blocks this signaling pathway in lung cancer cells both in vitro and in vivo. GZD856 strongly suppresses the proliferation of PDGFRα-amplified H1703 (PDGFRβ(-)) human lung cancer cells and demonstrates significant in vivo antitumor efficacy in a xenograft mouse model. Although GZD856 displays only limited in vitro antiproliferative efficiency against PDGFRα(-)/PDGFRβ(+) A549 lung cancer cells, it efficiently inhibits the in vivo growth and metastasis of A549 cancer cells in xenograft and orthotopic models, respectively. The promising in vivo antitumor activity of GZD856 in A549 models may result from its suppression of PDGFR-related microenvironment factors, such as recruitment of CAFs and collagen content in stromal cells. GZD856 may be considered as a promising new candidate for anti-lung cancer drug development.

  19. 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.

  20. The aqueous extract of Brucea javanica suppresses cell growth and alleviates tumorigenesis of human lung cancer cells by targeting mutated epidermal growth factor receptor

    PubMed Central

    Kim, Seung-Hun; Liu, Chun-Yen; Fan, Po-Wei; Hsieh, Chang-Heng; Lin, Hsuan-Yuan; Lee, Ming-Chung; Fang, Kang

    2016-01-01

    As a practical and safe herbal medicine, the seeds of Brucea javanica (L.) Merr., were used to cure patients suffering from infectious diseases such as malaria. Recent advances revealed that the herb could also be a useful cancer therapy agent. The study demonstrated that aqueous B. javanica (BJ) extract attenuated the growth of human non-small-lung cancer cells bearing mutant L858R/T790M epidermal growth factor receptor (EGFR). The reduced cell viability in H1975 cells was attributed to apoptosis. Transfection of EGFR small hairpin RNA reverted the sensitivities. When nude mice were fed BJ extract, the growth of xenograft tumors, as established by H1975 cells, was suppressed. Additional histological examination and fluorescence analysis of the resected tissues proved that the induced apoptosis mitigated tumor growth. The work proved that the BJ extract exerted its effectiveness by targeting lung cancer cells carrying mutated EGFR while alleviating tumorigenesis. Aqueous BJ extract is a good candidate to overcome drug resistance in patients undergoing target therapy. PMID:27843300

  1. Cerebral venous sinus thrombosis concomitant with leptomeningeal carcinomatosis, in a patient with epidermal growth factor receptor-mutated lung cancer.

    PubMed

    Oda, Naohiro; Sakugawa, Makoto; Bessho, Akihiro; Horiuchi, Takeshi; Hosokawa, Shinobu; Toyota, Yosuke; Fukamatsu, Nobuaki; Nishii, Kazuya; Watanabe, Yoichi

    2014-12-01

    A 64-year-old woman presented with dizziness, after two weeks of experiencing symptoms. Chest computed tomography revealed a peripheral nodule in her left upper lobe, and brain magnetic resonance imaging (MRI) demonstrated the presence of multiple brain masses. The patient underwent whole-brain radiotherapy based on a tentative diagnosis of lung cancer with multiple brain metastases. The diagnosis was confirmed by endobronchial biopsy as T4N3M1b, stage IV lung adenocarcinoma with an epidermal growth factor receptor mutation. On the 31st day of hospitalization, the patient developed severe headache. Subsequent magnetic resonance venography revealed defects in the superior sagittal, right sigmoid, and right transverse venous sinuses and the right internal jugular vein. Anticoagulation therapy with unfractionated heparin and warfarin was immediately administered following diagnosis of cerebral venous sinus thrombosis (CVST). Brain MRI demonstrated leptomeningeal gadolinium enhancement in front of the pons and medulla. Positive cerebrospinal fluid tumor cytology confirmed the diagnosis of leptomeningeal carcinomatosis. Following four weeks of antithrombotic therapy, complete thrombolysis was confirmed by magnetic resonance venography. Effective treatment with gefitinib was administered, and the patient survived for 10 months after the diagnosis of CVST and leptomeningeal carcinomatosis. Adequate early diagnosis and treatment of CVST enabled an excellent survival rate for the patient, despite leptomeningeal carcinomatosis. Following the development of headaches in patients with lung cancer, CVST, although rare, should be considered. Furthermore, following a diagnosis of CVST, leptomeningeal carcinomatosis should be investigated as an underlying cause.

  2. Is there a role for epidermal growth factor receptor tyrosine kinase inhibitors in epidermal growth factor receptor wild-type non-small cell lung cancer?

    PubMed Central

    Arriola, Edurne; Taus, Álvaro; Casadevall, David

    2015-01-01

    Non-small cell lung cancer (NSCLC) is the most common type of lung cancer with a world-wide annual incidence of around 1.3 million. The majority of patients are diagnosed with advanced disease and survival remains poor. However, relevant advances have occurred in recent years through the identification of biomarkers that predict for benefit of therapeutic agents. This is exemplified by the efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors for the treatment of EGFR mutant patients. These drugs have also shown efficacy in unselected populations but this point remains controversial. Here we have reviewed the clinical data that demonstrate a small but consistent subgroup of EGFR wild-type patients with NSCLC that obtain a clinical benefit from these drugs. Moreover, we review the biological rationale that may explain this benefit observed in the clinical setting. PMID:26266101

  3. Identification of a long non-coding RNA gene, growth hormone secretagogue receptor opposite strand, which stimulates cell migration in non-small cell lung cancer cell lines.

    PubMed

    Whiteside, Eliza J; Seim, Inge; Pauli, Jana P; O'Keeffe, Angela J; Thomas, Patrick B; Carter, Shea L; Walpole, Carina M; Fung, Jenny N T; Josh, Peter; Herington, Adrian C; Chopin, Lisa K

    2013-08-01

    The molecular mechanisms involved in non‑small cell lung cancer tumourigenesis are largely unknown; however, recent studies have suggested that long non-coding RNAs (lncRNAs) are likely to play a role. In this study, we used public databases to identify an mRNA-like, candidate long non-coding RNA, GHSROS (GHSR opposite strand), transcribed from the antisense strand of the ghrelin receptor gene, growth hormone secretagogue receptor (GHSR). Quantitative real-time RT-PCR revealed higher expression of GHSROS in lung cancer tissue compared to adjacent, non-tumour lung tissue. In common with many long non-coding RNAs, GHSROS is 5' capped and 3' polyadenylated (mRNA-like), lacks an extensive open reading frame and harbours a transposable element. Engineered overexpression of GHSROS stimulated cell migration in the A549 and NCI-H1299 non-small cell lung cancer cell lines, but suppressed cell migration in the Beas-2B normal lung-derived bronchoepithelial cell line. This suggests that GHSROS function may be dependent on the oncogenic context. The identification of GHSROS, which is expressed in lung cancer and stimulates cell migration in lung cancer cell lines, contributes to the growing number of non-coding RNAs that play a role in the regulation of tumourigenesis and metastatic cancer progression.

  4. 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.

  5. miR-22 inhibits tumor growth and metastasis by targeting ATP citrate lyase: evidence in osteosarcoma, prostate cancer, cervical cancer and lung cancer

    PubMed Central

    Liu, Jianjun; Song, Shaoli; Zhao, Xiaoping; Miao, Ping; Tang, Tingting; Wang, Lei; Liu, Weichun; Yang, Xiaodi; Dai, Kerong; Huang, Gang

    2016-01-01

    MicroRNAs (miRNAs) are non-coding small RNAs that function as negative regulators of gene expression involving in the tumor biology. ATP citrate lyase (ACLY), a key enzyme initiating de novo lipid synthesis, has been found to be upregulated in cancer cells, and its inhibition causes suppressive effects in a variety of tumors. At present, although several ACLY inhibitors have been reported, the potential role of miRNAs in interfering ACLY still needs further clarification. Herein, four different types of tumor cells including osteosarcoma, prostate, cervical and lung cancers were adopted in our study, and we have demonstrated that miR-22 directly downregulated ACLY. Moreover, miR-22 was proved to attenuate cancer cell proliferation and invasion, as well as promote cell apoptosis via inhibiting ACLY. Additionally, we confirmed the higher ACLY protein levels and the lower miR-22 expressions in hundreds of clinical samples of the four primary tumors, and a negative correlation relationship between ACLY and miR-22 was clarified. Finally, in the four animal models, we found that along with the loss of the ACLY expression, the miR-22-treated mice developed rather smaller tumors, less probabilities of distant metastasis, and fairly longer survivals. De novo lipogenesis suppression triggered by miR-22-ACLY axis may contribute to the inhibition of tumor growth and metastasis. These findings provide unequivocal proofs that miR-22 is responsible for the posttranscriptional regulation of ACLY, which yields promising therapeutic effects in osteosarcoma, prostate, cervical and lung cancers. PMID:27317765

  6. Rig-G is a growth inhibitory factor of lung cancer cells that suppresses STAT3 and NF-κB

    PubMed Central

    Wang, Xuan; Bals, Robert; Wu, Junlu; Quan, Wenqiang; Yao, Yiwen; Zhang, Yu; Zhou, Hong; Wu, Kaiyin

    2016-01-01

    The expression of the retinoic acid-induced G (Rig-G) gene, an all trans retinoic acid (ATRA)-inducible gene, was observed in multiple cancer cells, including lung cancer cells. However, whether Rig-G is a tumor suppressor in lung cancer is unknown. Here, we found that ectopic expression of Rig-G can lead to a significant decrease in proliferation of lung cancer cells, resulting in an inhibition of tumor growth. Rig-G knockdown results in a modest increase in cell proliferation, as well as confers an increase in colony formation. Furthermore, transcriptome and pathway analyses of cancer cells revealed a fundamental impact of Rig-G on various growth signaling pathways, including the NF-κB pathway. Rig-G inhibits NF-κB activity by suppressing STAT3 in lung cancer cells. The downregulation of miR21 and miR181b-1 and subsequent activation of PTEN/Akt and CYLD/IκB signaling axis leading to decreased NF-κB activity required to maintain the tumor-inhibiting effect of Rig-G.. Our findings contribute to a better understanding of the antitumor effect mechanism of Rig-G, as well as offer a novel strategy for lung cancer therapy. PMID:27602766

  7. Rig-G is a growth inhibitory factor of lung cancer cells that suppresses STAT3 and NF-κB.

    PubMed

    Li, Dong; Sun, Junjun; Liu, Wenfang; Wang, Xuan; Bals, Robert; Wu, Junlu; Quan, Wenqiang; Yao, Yiwen; Zhang, Yu; Zhou, Hong; Wu, Kaiyin

    2016-10-04

    The expression of the retinoic acid-induced G (Rig-G) gene, an all trans retinoic acid (ATRA)-inducible gene, was observed in multiple cancer cells, including lung cancer cells. However, whether Rig-G is a tumor suppressor in lung cancer is unknown. Here, we found that ectopic expression of Rig-G can lead to a significant decrease in proliferation of lung cancer cells, resulting in an inhibition of tumor growth. Rig-G knockdown results in a modest increase in cell proliferation, as well as confers an increase in colony formation. Furthermore, transcriptome and pathway analyses of cancer cells revealed a fundamental impact of Rig-G on various growth signaling pathways, including the NF-κB pathway. Rig-G inhibits NF-κB activity by suppressing STAT3 in lung cancer cells. The downregulation of miR21 and miR181b-1 and subsequent activation of PTEN/Akt and CYLD/IκB signaling axis leading to decreased NF-κB activity required to maintain the tumor-inhibiting effect of Rig-G.. Our findings contribute to a better understanding of the antitumor effect mechanism of Rig-G, as well as offer a novel strategy for lung cancer therapy.

  8. cAMP/CREB-regulated LINC00473 marks LKB1-inactivated lung cancer and mediates tumor growth

    PubMed Central

    Chen, Zirong; Lin, Shuibin; Cao, Chunxia; Gimbrone, Nicholas T.; Yang, Rongqiang; Fu, Dongtao A.; Carper, Miranda B.; Haura, Eric B.; Schabath, Matthew B.; Cress, W. Douglas; Kaye, Frederic J.

    2016-01-01

    The LKB1 tumor suppressor gene is frequently mutated and inactivated in non–small cell lung cancer (NSCLC). Loss of LKB1 promotes cancer progression and influences therapeutic responses in preclinical studies; however, specific targeted therapies for lung cancer with LKB1 inactivation are currently unavailable. Here, we have identified a long noncoding RNA (lncRNA) signature that is associated with the loss of LKB1 function. We discovered that LINC00473 is consistently the most highly induced gene in LKB1-inactivated human primary NSCLC samples and derived cell lines. Elevated LINC00473 expression correlated with poor prognosis, and sustained LINC00473 expression was required for the growth and survival of LKB1-inactivated NSCLC cells. Mechanistically, LINC00473 was induced by LKB1 inactivation and subsequent cyclic AMP–responsive element–binding protein (CREB)/CREB-regulated transcription coactivator (CRTC) activation. We determined that LINC00473 is a nuclear lncRNA and interacts with NONO, a component of the cAMP signaling pathway, thereby facilitating CRTC/CREB-mediated transcription. Collectively, our study demonstrates that LINC00473 expression potentially serves as a robust biomarker for tumor LKB1 functional status that can be integrated into clinical trials for patient selection and treatment evaluation, and implicates LINC00473 as a therapeutic target for LKB1-inactivated NSCLC. PMID:27140397

  9. Growth inhibitory effects of miR-221 and miR-222 in non-small cell lung cancer cells

    PubMed Central

    Yamashita, Ryo; Sato, Mitsuo; Kakumu, Tomohiko; Hase, Tetsunari; Yogo, Naoyuki; Maruyama, Eiichi; Sekido, Yoshitaka; Kondo, Masashi; Hasegawa, Yoshinori

    2015-01-01

    Both pro- and anti-oncogenic roles of miR-221 and miR-222 microRNAs are reported in several types of human cancers. A previous study suggested their oncogenic role in invasiveness in lung cancer, albeit only one cell line (H460) was used. To further evaluate involvement of miR-221 and miR-222 in lung cancer, we investigated the effects of miR-221 and miR-222 overexpression on six lung cancer cell lines, including H460, as well as one immortalized normal human bronchial epithelial cell line, HBEC4. miR-221 and miR-222 induced epithelial-to-mesenchymal transition (EMT)-like changes in a minority of HBEC4 cells but, unexpectedly, both the microRNAs rather suppressed their invasiveness. Consistent with the prior report, miR-221 and miR-222 promoted growth in H460; however, miR-221 suppressed growth in four other cell lines with no effects in one, and miR-222 suppressed growth in three cell lines but promoted growth in two. These are the first results to show tumor-suppressive effects of miR-221 and miR-222 in lung cancer cells, and we focused on clarifying the mechanisms. Cell cycle and apoptosis analyses revealed that growth suppression by miR-221 and miR-222 occurred through intra-S-phase arrest and/or apoptosis. Finally, lung cancer cell lines transfected with miR-221 or miR-222 became more sensitive to the S-phase targeting drugs, possibly due to an increased S-phase population. In conclusion, our data are the first to show tumor-suppressive effects of miR-221 and miR-222 on lung cancer, warranting testing their potential as therapeutics for the disease. PMID:25641933

  10. Growth inhibitory effects of miR-221 and miR-222 in non-small cell lung cancer cells.

    PubMed

    Yamashita, Ryo; Sato, Mitsuo; Kakumu, Tomohiko; Hase, Tetsunari; Yogo, Naoyuki; Maruyama, Eiichi; Sekido, Yoshitaka; Kondo, Masashi; Hasegawa, Yoshinori

    2015-04-01

    Both pro- and anti-oncogenic roles of miR-221 and miR-222 microRNAs are reported in several types of human cancers. A previous study suggested their oncogenic role in invasiveness in lung cancer, albeit only one cell line (H460) was used. To further evaluate involvement of miR-221 and miR-222 in lung cancer, we investigated the effects of miR-221 and miR-222 overexpression on six lung cancer cell lines, including H460, as well as one immortalized normal human bronchial epithelial cell line, HBEC4. miR-221 and miR-222 induced epithelial-to-mesenchymal transition (EMT)-like changes in a minority of HBEC4 cells but, unexpectedly, both the microRNAs rather suppressed their invasiveness. Consistent with the prior report, miR-221 and miR-222 promoted growth in H460; however, miR-221 suppressed growth in four other cell lines with no effects in one, and miR-222 suppressed growth in three cell lines but promoted growth in two. These are the first results to show tumor-suppressive effects of miR-221 and miR-222 in lung cancer cells, and we focused on clarifying the mechanisms. Cell cycle and apoptosis analyses revealed that growth suppression by miR-221 and miR-222 occurred through intra-S-phase arrest and/or apoptosis. Finally, lung cancer cell lines transfected with miR-221 or miR-222 became more sensitive to the S-phase targeting drugs, possibly due to an increased S-phase population. In conclusion, our data are the first to show tumor-suppressive effects of miR-221 and miR-222 on lung cancer, warranting testing their potential as therapeutics for the disease.

  11. Radiotherapy for lung cancer

    SciTech Connect

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

    1985-05-01

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

  12. Alterations of tumor microenvironment by carbon monoxide impedes lung cancer growth

    PubMed Central

    Nemeth, Zsuzsanna; Csizmadia, Eva; Vikstrom, Lisa; Li, Mailin; Bisht, Kavita; Feizi, Alborz; Otterbein, Sherrie; Zuckerbraun, Brian; Costa, Daniel B.; Pandolfi, Pier Paolo; Fillinger, Janos; Döme, Balazs; Otterbein, Leo E.; Wegiel, Barbara

    2016-01-01

    We hypothesized that tumor-associated macrophages (TAMs) are controlled by the diffusible gas carbon monoxide (CO). We demonstrate that induction of apoptosis in lung tumors treated with low doses of CO is associated with increased CD86 expression and activation of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinases (Erk) 1/2 pathway in tumor microenvironment. Presence of CD86-positive cells was required for the anti-tumoral effects of CO in established A549 xenografts. We show that the effects of CO on tumor stroma and reprogramming of macrophages towards the anti-tumoral phenotype is mediated by reactive oxygen species (ROS)-dependent activation of MAPK/Erk1/2-c-myc pathway as well as Notch 1-dependent negative feedback on the metabolic enzyme heme oxygenase-1 (HO-1). We find a similar negative correlation between HO-1 and active MAPK-Erk1/2 levels in human lung cancer specimens. In summary, we describe novel non-cell autonomous mechanisms by which the diffusible gas CO dictates changes in the tumor microenvironment through the modulation of macrophages. PMID:26993595

  13. Lung Cancer Brain Metastases.

    PubMed

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

    2015-01-01

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

  14. A Specific Mixture of Nutrients Suppresses Ovarian Cancer A-2780 Tumor Incidence, Growth, and Metastasis to Lungs.

    PubMed

    Roomi, Mohd Waheed; Kalinovsky, Tatiana; Rath, Matthias; Niedzwiecki, Aleksandra

    2017-03-18

    with EPQ, and H & E staining showed no morphological changes below 500 μg/mL EPQ. These results suggest that EPQ has therapeutic potential in the treatment of ovarian cancer by significantly suppressing ovarian tumor incidence and growth and lung metastasis, and by inhibiting MMP-9 secretion and invasion of A-2780 ovarian cancer cells.

  15. A Specific Mixture of Nutrients Suppresses Ovarian Cancer A-2780 Tumor Incidence, Growth, and Metastasis to Lungs

    PubMed Central

    Roomi, Mohd Waheed; Kalinovsky, Tatiana; Rath, Matthias; Niedzwiecki, Aleksandra

    2017-01-01

    with EPQ, and H & E staining showed no morphological changes below 500 μg/mL EPQ. These results suggest that EPQ has therapeutic potential in the treatment of ovarian cancer by significantly suppressing ovarian tumor incidence and growth and lung metastasis, and by inhibiting MMP-9 secretion and invasion of A-2780 ovarian cancer cells. PMID:28335466

  16. Effective growth-suppressive activity of maternal embryonic leucine-zipper kinase (MELK) inhibitor against small cell lung cancer

    PubMed Central

    Inoue, Hiroyuki; Kato, Taigo; Olugbile, Sope; Tamura, Kenji; Chung, Suyoun; Miyamoto, Takashi; Matsuo, Yo; Salgia, Ravi; Nakamura, Yusuke; Park, Jae-Hyun

    2016-01-01

    Maternal embryonic leucine zipper kinase (MELK), that plays a critical role in maintenance of cancer stem cells (CSCs), is predominantly expressed in various types of human cancer including small cell lung cancer (SCLC). SCLC usually acquires resistance to anti-cancer drugs and portends dismal prognosis. We have delineated roles of MELK in development/progression of SCLC and examined anti-tumor efficacy of OTS167, a highly potent MELK inhibitor, against SCLC. MELK expression was highly upregulated in both SCLC cell lines and primary tumors. siRNA-mediated MELK knockdown induced significant growth inhibition in SCLC cell lines. Concordantly, treatment with OTS167 exhibited strong cytotoxicity against eleven SCLC cell lines with IC50 of < 10 nM. As similar to siRNA knockdown, OTS167 treatment induced cytokinetic defects with intercellular bridges, and in some cell lines we observed formation of neuronal protrusions accompanied with increase of a neuronal differentiation marker (CD56), indicating that the compound induced differentiation of cancer cells to neuron-like cells. Furthermore, the MELK inhibition decreased its downstream FOXM1 activity and Akt expression in SCLC cells, and led to apoptotic cell death. OTS167 appeared to be more effective to CSCs as measured by the sphere formation assay, thus MELK inhibition might become a promising treatment modality for SCLC. PMID:26871945

  17. [Epidemiology of lung cancer].

    PubMed

    Becker, N

    2010-08-01

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

  18. Targeted Expression of miR-7 Operated by TTF-1 Promoter Inhibited the Growth of Human Lung Cancer through the NDUFA4 Pathway.

    PubMed

    Lei, Liangyu; Chen, Chao; Zhao, Juanjuan; Wang, HaiRong; Guo, Mengmeng; Zhou, Ya; Luo, Junming; Zhang, Jidong; Xu, Lin

    2017-03-17

    Targeted expression of gene technique is an important therapeutic strategy for lung cancer. MicroRNA-7 has been well documented as a promising tumor suppressor but never been test in specific gene-promoter-targeted expression in cancer gene therapy. Here, we first evaluated the efficacy of miR-7 expression operated by the promoter of TTF-1, a lineage-specific oncogene in lung cancer, in vitro using an eukaryotic vector of TTF-1-promoter-operated expression of miR-7 (termed as p-T-miR-7). Interestingly, using a nude mice model, the growth and metastasis of human lung cancer cells in vivo were significantly reduced in remote hypodermic injection of the p-T-miR-7 group, accompanied by increased expression of miR-7 and reduced transduction of the Akt and Erk pathway in situ. Mechanism aspect, global gene expression analysis showed that downregulation of NDUFA4, a novel target of miR-7, contributed to the effects of miR-7 expression operated by TTF-1 promoter on the growth and metastasis of human lung cancer cells, as well as altered transduction of the Akt and Erk pathway. Finally, there was no significant difference in weight or histopathology of other organs. These data provided a basis for development of novel modality of miRNA-based targeted expression therapy against clinical lung cancer.

  19. Nutrition aspects of lung cancer.

    PubMed

    Cranganu, Andreea; Camporeale, Jayne

    2009-12-01

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

  20. miR-203 enhances let-7 biogenesis by targeting LIN28B to suppress tumor growth in lung cancer

    PubMed Central

    Zhou, Yong; Liang, Hongwei; Liao, Zhicong; Wang, Yanbo; Hu, Xiuting; Chen, Xi; Xu, Lin; Hu, Zhibin

    2017-01-01

    Human cancers often exhibit increased microRNA (miRNA) biogenesis and global aberrant expression of miRNAs; thus, targeting the miRNA biogenesis pathway represents a novel strategy for cancer therapy. Here, we report that miR-203 enhances the biogenesis of tumor suppressor let-7 in lung cancer by directly targeting LIN28B. Specially, we found that the LIN28B protein levels were dramatically increased in lung cancer tissues, but its mRNA levels did not differ significantly, suggesting that a post-transcriptional mechanism is involved in LIN28B regulation. Interestingly, miR-203 overexpression was accompanied by massive upregulation of a group of miRNAs, especially let-7, and the let-7 expression level was concordant with the miR-203 expression in lung cancer tissues, implying its biological relevance. Furthermore, we showed that miR-203 played a critical role in inhibiting the proliferation and promoting the apoptosis of lung cancer cells by suppressing LIN28B and enhancing let-7 biogenesis. In summary, our results establish a novel mechanism by which miR-203, LIN28B and let-7 are tightly linked to form a regulatory network in lung cancer cells. The findings shed light on the role of a specific miRNA as a modulator of miRNA biogenesis and provide basis for developing new strategies for lung cancer therapy. PMID:28218277

  1. miR-203 enhances let-7 biogenesis by targeting LIN28B to suppress tumor growth in lung cancer.

    PubMed

    Zhou, Yong; Liang, Hongwei; Liao, Zhicong; Wang, Yanbo; Hu, Xiuting; Chen, Xi; Xu, Lin; Hu, Zhibin

    2017-02-20

    Human cancers often exhibit increased microRNA (miRNA) biogenesis and global aberrant expression of miRNAs; thus, targeting the miRNA biogenesis pathway represents a novel strategy for cancer therapy. Here, we report that miR-203 enhances the biogenesis of tumor suppressor let-7 in lung cancer by directly targeting LIN28B. Specially, we found that the LIN28B protein levels were dramatically increased in lung cancer tissues, but its mRNA levels did not differ significantly, suggesting that a post-transcriptional mechanism is involved in LIN28B regulation. Interestingly, miR-203 overexpression was accompanied by massive upregulation of a group of miRNAs, especially let-7, and the let-7 expression level was concordant with the miR-203 expression in lung cancer tissues, implying its biological relevance. Furthermore, we showed that miR-203 played a critical role in inhibiting the proliferation and promoting the apoptosis of lung cancer cells by suppressing LIN28B and enhancing let-7 biogenesis. In summary, our results establish a novel mechanism by which miR-203, LIN28B and let-7 are tightly linked to form a regulatory network in lung cancer cells. The findings shed light on the role of a specific miRNA as a modulator of miRNA biogenesis and provide basis for developing new strategies for lung cancer therapy.

  2. Silencing survivin expression inhibits the tumor growth of non-small-cell lung cancer cells in vitro and in vivo.

    PubMed

    Zhang, Kejian; Li, Yang; Liu, Wei; Gao, Xinliang; Zhang, Kewei

    2015-01-01

    Survivin is a promising anticancer therapeutic target due to its important role in the inhibition of apoptosis of tumor cells. However, little is currently known about its role in non small cell lung cancer (NSCLC). The present study evaluated whether the downregulation of survivin expression would affect cell proliferation, cell cycle distribution, apoptosis and colony formation of NSCLC. A recombinant lentiviral small hairpin RNA (shRNA) expression vector, which specifically targeted survivin, was constructed and transfected into the A549 human NSCLC cell line. Quantitative polymerase chain reaction and western blotting were used to determine the mRNA and protein expression levels of survivin, 48 h following the knockdown of survivin expression. Cell proliferation, apoptosis, cell cycle distribution and colony formation were determined following the downregulation of survivin by shRNA. In addition, A549 cells were injected into nude mice, and the effects of shRNA targeting the survivin gene on tumor growth were assessed. Downregulation of survivin expression, using the RNA silencing approach in A549 tumor cells, significantly suppressed the proliferation and colony formation ability of the cells, and induced tumor apoptosis in vitro. The nude mice inoculated with A549 cells developed cancer, and treatment with shRNA targeting survivin markedly inhibited the growth of these cancers, with no obvious side effects. The results of the present study suggest that suppression of survivin expression by RNA interference may induce NSCLC apoptosis, and provide a novel approach for anticancer gene therapy.

  3. MicroRNA-222 promotes human non-small cell lung cancer H460 growth by targeting p27.

    PubMed

    Zhong, Chongjun; Ding, Shengguang; Xu, Yiming; Huang, Haitao

    2015-01-01

    Two highly homologous microRNAs (miRNAs, miRs), miR-222 and miR-221, act as a cluster in cellular regulation. We have previously reported that miR-221 promoted the growth of human non-small cell lung cancer cell line H460. However, the role of miR-222 in regulating the growth of H460 is unclear. H460 cells were transfected with miR-222 mimics, inhibitors or their negative controls and their effects were confirmed by Real-time quantitative reverse transcription polymerase chain reactions (qRT-PCRs). Cell viability was assessed by Cell Counting Kit-8 (CCK-8) while cell proliferation was determined by 5-Ethynyl-2'-deoxyuridine (EdU) assay. P27 and P57, two putative targets of miR-222, were checked by qRT-PCRs. We found that miR-222 overexpression increased cell viability and proliferative rate in H460 cells while opposite effects were obtained by down-regulation of miR-222. P27 but not P57 was identified as a potential target of miR-222 in H460 cells as P27 was negatively regulated by miR-222 in the protein level. In summary, the present study indicates that miR-222 controls the growth of H460 likely by targeting P27. Inhibition of miR-222 might be a novel therapy for human non-small cell lung cancer.

  4. Neuroendocrine Cancer-Specific Up-Regulating Mechanism of Insulin-Like Growth Factor Binding Protein-2 in Small Cell Lung Cancer

    PubMed Central

    Yazawa, Takuya; Sato, Hanako; Shimoyamada, Hiroaki; Okudela, Koji; Woo, Tetsukan; Tajiri, Michihiko; Ogura, Takashi; Ogawa, Nobuo; Suzuki, Takehisa; Mitsui, Hideaki; Ishii, Jun; Miyata, Chie; Sakaeda, Masashi; Goto, Kazuya; Kashiwagi, Korehito; Masuda, Munetaka; Takahashi, Takashi; Kitamura, Hitoshi

    2009-01-01

    Small cell lung cancer (SCLC) exhibits insulin-like growth factor-dependent growth. SCLC is the most aggressive among known in vivo lung cancers, whereas in vitro growth of SCLC is paradoxically slow as compared with that of non-SCLC (NSCLC). In this study, we demonstrate that SCLC cells overexpress insulin-like growth factor binding protein (IGFBP)-2 via NeuroD, a neuroendocrine cell-specific transcription factor. Chromatin immunoprecipitation, electrophoretic mobility shift, and IGFBP-2 promoter assays all revealed that NeuroD binds to the E-box in the 5′-untranslated region of IGFBP-2. A NeuroD transgene in both airway epithelial and NSCLC cells up-regulated the transcription of IGFBP-2 and retarded cell growth. Recombinant IGFBP-2 repressed the growth of both airway epithelial and NSCLC cells in a dose-dependent manner. A NeuroD-specific small interfering RNA repressed IGFBP-2 expression in SCLC, and neutralization of IGFBP-2 and an IGFBP-2-specific small interfering RNA increased SCLC cell growth. Pathological samples of SCLC also expressed IGFBP-2 abundantly, as compared with NSCLC, and showed only rare (8%) IGFBP-2 promoter methylation, whereas the IGFBP-2 promoter was methylated in 71% of adenocarcinomas and 29% of squamous cell carcinomas. These findings suggest that 1) SCLC has an IGFBP-2 overexpression mechanism distinct from NSCLC, 2) secreted IGFBP-2 contributes to the slow growth of SCLC in vitro, and 3) the epigenetic alterations in the IGFBP-2 promoter contribute to the striking differences in IGFBP-2 expression between SCLC and NSCLC in vivo. PMID:19679880

  5. γ-Glutamylcyclotransferase Knockdown Inhibits Growth of Lung Cancer Cells Through G0/G1 Phase Arrest.

    PubMed

    Lin, Zhifeng; Xiong, Liwen; Zhou, Jianhua; Wang, Jin; Li, Zhao; Hu, Haiyang; Lin, Qiang

    2015-06-01

    Lung cancer as an aggressive type tumor is rapidly growing and has become the leading cause of cancer-related death worldwide. γ-Glutamylcyclotransferase (GGCT) has been shown as a diagnostic marker in various cancers. To reveal whether there is a correlation between GGCT and lung cancer, GGCT expression in human lung cancer cell lines was first determined by real-time quantitative PCR and western blot. GGCT is expressed in all tested lung cancer cell lines, A549, H1299, and H460. Then, a lentivirus-based system was applied to knock down GGCT in A549 cells, which were thus divided into Lv-shGGCT, Lv-shCon, and Con (noninfected) groups. Methylthiazol tetrazolium assay showed that the cell proliferation was decreased by over 50% in the Lv-shGGCT group compared with controls. The size and number of colonies were dramatically reduced in the GGCT knockdown group, as measured by colony formation assay. Moreover, A549 cells infected with Lv-shGGCT were arrested in the G0/G1 phase as assayed by flow cytometry. Furthermore, the expression levels of CDK4, CDK6, and cyclin D1 were decreased and the cleaved level of PARP was increased in GGCT knockdown cells. In conclusion, GGCT plays a critical role in lung cancer cell proliferation and may be a potential cancer therapeutic target.

  6. Therapeutic inhibition of TRF1 impairs the growth of p53-deficient K-RasG12V-induced lung cancer by induction of telomeric DNA damage.

    PubMed

    García-Beccaria, María; Martínez, Paula; Méndez-Pertuz, Marinela; Martínez, Sonia; Blanco-Aparicio, Carmen; Cañamero, Marta; Mulero, Francisca; Ambrogio, Chiara; Flores, Juana M; Megias, Diego; Barbacid, Mariano; Pastor, Joaquín; Blasco, Maria A

    2015-07-01

    Telomeres are considered anti-cancer targets, as telomere maintenance above a minimum length is necessary for cancer growth. Telomerase abrogation in cancer-prone mouse models, however, only decreased tumor growth after several mouse generations when telomeres reach a critically short length, and this effect was lost upon p53 mutation. Here, we address whether induction of telomere uncapping by inhibition of the TRF1 shelterin protein can effectively block cancer growth independently of telomere length. We show that genetic Trf1 ablation impairs the growth of p53-null K-Ras(G12V)-induced lung carcinomas and increases mouse survival independently of telomere length. This is accompanied by induction of telomeric DNA damage, apoptosis, decreased proliferation, and G2 arrest. Long-term whole-body Trf1 deletion in adult mice did not impact on mouse survival and viability, although some mice showed a moderately decreased cellularity in bone marrow and blood. Importantly, inhibition of TRF1 binding to telomeres by small molecules blocks the growth of already established lung carcinomas without affecting mouse survival or tissue function. Thus, induction of acute telomere uncapping emerges as a potential new therapeutic target for lung cancer.

  7. Nutritional aspects regarding lung cancer chemoprevention.

    PubMed

    Thanopoulou, E; Baltayiannis, N; Lykogianni, V

    2006-01-01

    Lung cancer is still one of the major causes of cancer-related deaths and its mortality figures argue powerfully for new approaches to control this leading cancer threat. Chemoprevention can be defined as the use of specific agents to reverse, or prevent premalignancy from progressing to invasive cancer. The use of foods and dietary supplements present a safe chemopreventive strategy. Data for this review were identified by searches of PubMed and references from relevant articles. Articles were identified by use of the search terms "lung cancer", "chemoprevention", "carcinogenesis", and "retinoids". Only papers published in English were included. Trials in lung cancer chemoprevention have so far produced either neutral or harmful primary endpoint results, whether in the primary, secondary, or tertiary settings. Lung cancer was not prevented by beta-carotene, alpha-tocopherol, retinol, retinyl palmitate, N-acetylcysteine, or isotretinoin in smokers. Ongoing trials may help define new avenues for chemoprevention. The concept of chemoprevention in lung cancer is still in its infancy, but in the future it may have a significant impact on the incidence and mortality of lung cancer. In addition to epidemiologic studies, basic science research to detect mechanisms and evaluate the chemopreventive potential of food components is necessary. The overwhelming evidence of a major role of nutrition in carcinogenesis, the many leads that nutritional intervention may reduce cancer incidence, and the growth and increasing sophistication of clinical trials networks point to a very promising future for nutritional intervention trials leading to substantial public benefit.

  8. The role of posttraumatic growth and timing of quitting smoking as moderators of the relationship between stigma and psychological distress among lung cancer survivors who are former smokers

    PubMed Central

    Shen, Megan Johnson; Coups, Elliot J.; Li, Yuelin; Holland, Jimmie C.; Hamann, Heidi A.; Ostroff, Jamie S.

    2015-01-01

    Objective Patients diagnosed with lung cancer report high levels of stigma and psychological distress. This study examined posttraumatic growth among lung cancer survivors as a potential buffer against this relationship between stigma and psychological distress and examined how these relationships differed by the timing of quitting smoking (pre versus post-diagnosis). Methods Stages IA and IB non-small-cell lung cancer survivors (N= 141) who were former smokers, 1–6 years post-treatment, and had no evidence of disease completed standardized questionnaires assessing stigma, posttraumatic growth, timing of quitting smoking history, and psychological distress. Results Hierarchical linear regression and simple slope analyses indicated that among those who quit smoking prior to diagnosis (pre-diagnosis quitters), stigma had a positive association with psychological distress at high levels of posttraumatic growth (p = 0.003) and had a positive (but non-significant) association with psychological distress among those with low levels of posttraumatic growth (p = 0.167). Among those who quit smoking after diagnosis (post-diagnosis quitters), stigma had a positive association with psychological distress among those with low levels of posttraumatic growth (p = 0.004) but had no relationship among those with high levels of posttraumatic growth (p = 0.880). Conclusions Findings indicate that posttraumatic growth buffers against the negative effects of stigma on psychological distress but only among post-diagnosis quitters. Future interventions could focus on fostering posttraumatic growth as a way to decrease the negative effects of stigma. PMID:25345591

  9. Metformin inhibits growth and enhances radiation response of non-small cell lung cancer (NSCLC) through ATM and AMPK

    PubMed Central

    Storozhuk, Y; Hopmans, S N; Sanli, T; Barron, C; Tsiani, E; Cutz, J-C; Pond, G; Wright, J; Singh, G; Tsakiridis, T

    2013-01-01

    Background: We examined the potential of metformin (MET) to enhance non-small cell lung cancer (NSCLC) responses to ionising radiation (IR). Methods: Human NSCLC cells, mouse embryonic fibroblasts from wild-type and AMP-activated kinase (AMPK) α1/2-subunit−/− embryos (AMPKα1/2−/−-MEFs) and NSCLC tumours grafted into Balb/c-nude mice were treated with IR and MET and subjected to proliferation, clonogenic, immunoblotting, cell cycle and apoptosis assays and immunohistochemistry (IHC). Results: Metformin (2.5 μℳ–5 mℳ) inhibited proliferation and radio-sensitised NSCLC cells. Metformin (i) activated the ataxia telengiectasia-mutated (ATM)–AMPK–p53/p21cip1 and inhibited the Akt–mammalian target of rapamycin (mTOR)–eIF4E-binding protein 1 (4EBP1) pathways, (ii) induced G1 cycle arrest and (iii) enhanced apoptosis. ATM inhibition blocked MET and IR activation of AMPK. Non-small cell lung cancer cells with inhibited AMPK and AMPKα1/2−/−-MEFs were resistant to the antiproliferative effects of MET and IR. Metformin or IR inhibited xenograft growth and combined treatment enhanced it further than each treatment alone. Ionising radiation and MET induced (i) sustained activation of ATM–AMPK–p53/p21cip1 and inhibition of Akt–mTOR–4EBP1 pathways in tumours, (ii) reduced expression of angiogenesis and (iii) enhanced expression of apoptosis markers. Conclusion: Clinically achievable MET doses inhibit NSCLC cell and tumour growth and sensitise them to IR. Metformin and IR mediate their action through an ATM–AMPK-dependent pathway. Our results suggest that MET can be a clinically useful adjunct to radiotherapy in NSCLC. PMID:23632475

  10. Inhibition of lung cancer cell growth and induction of apoptosis after reexpression of 3p21.3 candidate tumor suppressor gene SEMA3B

    PubMed Central

    Tomizawa, Yoshio; Sekido, Yoshitaka; Kondo, Masashi; Gao, Boning; Yokota, Jun; Roche, Joëlle; Drabkin, Harry; Lerman, Michael I.; Gazdar, Adi F.; Minna, John D.

    2001-01-01

    Semaphorins SEMA3B and its homologue SEMA3F are 3p21.3 candidate tumor suppressor genes (TSGs), the expression of which is frequently lost in lung cancers. To test the TSG candidacy of SEMA3B and SEMA3F, we transfected them into lung cancer NCI-H1299 cells, which do not express either gene. Colony formation of H1299 cells was reduced 90% after transfection with wild-type SEMA3B compared with the control vector. By contrast, only 30–40% reduction in colony formation was seen after the transfection of SEMA3F or SEMA3B variants carrying lung cancer-associated single amino acid missense mutations. H1299 cells transfected with wild-type but not mutant SEMA3B underwent apoptosis. We found that lung cancers (n = 34) always express the neuropilin-1 receptor for secreted semaphorins, whereas 82% expressed the neuropilin-2 receptor. Because SEMA3B and SEMA3F are secreted proteins, we tested conditioned medium from COS-7 cells transfected with SEMA3B and SEMA3F and found that medium from wild-type SEMA3B transfectants reduced the growth of several lung cancer lines 30–90%, whereas SEMA3B mutants or SEMA3F had little effect in the same assay. Sequencing of sodium bisulfite-treated DNA showed dense methylation of CpG sites in the SEMA3B 5′ region of lung cancers not expressing SEMA3B but no methylation in SEMA3B-expressing tumors. These results are consistent with SEMA3B functioning as a TSG, the expression of which is inactivated frequently in lung cancers by allele loss and promoter region methylation. PMID:11717452

  11. Lung cancer susceptibility among atomic bomb survivors in relation to CA repeat number polymorphism of epidermal growth factor receptor gene and radiation dose.

    PubMed

    Yoshida, Kengo; Nakachi, Kei; Imai, Kazue; Cologne, John B; Niwa, Yasuharu; Kusunoki, Yoichiro; Hayashi, Tomonori

    2009-12-01

    Lung cancer is a leading cause of cancer death worldwide. Prevention could be improved by identifying susceptible individuals as well as improving understanding of interactions between genes and etiological environmental agents, including radiation exposure. The epidermal growth factor receptor (EGFR)-signaling pathway, regulating cellular radiation sensitivity, is an oncogenic cascade involved in lung cancer, especially adenocarcinoma. The cytosine adenine (CA) repeat number polymorphism in the first intron of EGFR has been shown to be inversely correlated with EGFR production. It is hypothesized that CA repeat number may modulate individual susceptibility to lung cancer. Thus, we carried out a case-cohort study within the Japanese atomic bomb (A-bomb) survivor cohort to evaluate a possible association of CA repeat polymorphism with lung cancer risk in radiation-exposed or negligibly exposed (<5 mGy) A-bomb survivors. First, by dividing study subjects into Short and Long genotypes, defined as the summed CA repeat number of two alleles < or = 37 and > or = 38, respectively, we found that the Short genotype was significantly associated with an increased risk of lung cancer, specifically adenocarcinoma, among negligibly exposed subjects. Next, we found that prior radiation exposure significantly enhanced lung cancer risk of survivors with the Long genotype, whereas the risk for the Short genotype did not show any significant increase with radiation dose, resulting in indistinguishable risks between these genotypes at a high radiation dose. Our findings imply that the EGFR pathway plays a crucial role in assessing individual susceptibility to lung adenocarcinoma in relation to radiation exposure.

  12. Pulmonary Rehabilitation in Lung Cancer.

    PubMed

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

    2016-10-01

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

  13. Immunotherapy in Lung Cancer.

    PubMed

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

    2017-02-01

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

  14. Transforming growth factor-β1 induces EMT by the transactivation of epidermal growth factor signaling through HA/CD44 in lung and breast cancer cells

    PubMed Central

    LI, LINGMEI; QI, LISHA; LIANG, ZHIJIE; SONG, WANGZHAO; LIU, YANXUE; WANG, YALEI; SUN, BAOCUN; ZHANG, BIN; CAO, WENFENG

    2015-01-01

    Epithelial-mesenchymal transition (EMT), a process closely related to tumor development, is regulated by a variety of signaling pathways and growth factors, such as transforming growth factor-β1 (TGF-β1) and epidermal growth factor (EGF). Hyaluronan (HA) has been shown to induce EMT through either TGF-β1 or EGF signaling and to be a regulator of the crosstalk between these two pathways in fibroblasts. In this study, in order to clarify whether HA has the same effect in tumor cells, we utilized the lung cancer cell line, A549, and the breast cancer cell line, MCF-7, and found that the effects of stimulation with TGF-β1 were more potent than those of EGF in regulating the expression of EMT-associated proteins and in enhancing cell migration and invasion. In addition, we observed that TGF-β1 activated EGF receptor (EGFR) and its downstream AKT and extracellular signal-regulated kinase (ERK) pathways. Furthermore, we found that TGF-β1 upregulated the expression of hyaluronan synthases (HAS1, HAS2 and HAS3) and promoted the expression of CD44, a cell surface receptor for HA, which interacts with EGFR, resulting in the activation of the downstream AKT and ERK pathways. Conversely, treatment with 4-methylumbelliferone (4-MU; an inhibitor of HAS) prior to stimulation with TGF-β1, inhibited the expression of CD44 and EGFR, abolished the interaction between CD44 and EGFR. Furthermore, the use of shRNA targeting CD44 impaired the expression of EGFR, deactivated the AKT and ERK pathways, reversed EMT and decreased the migration and invasion ability of cells. In conclusion, our data demonstrate that TGF-β1 induces EMT by the transactivation of EGF signaling through HA/CD44 in lung and breast cancer cells. PMID:26005723

  15. Toll-like receptor 5 agonist inhibition of growth of A549 lung cancer cells in vivo in a Myd88 dependent manner.

    PubMed

    Zhou, Shi-Xiang; Li, Feng-Sheng; Qiao, Yu-Lei; Zhang, Xue-Qing; Wang, Zhi-Dong

    2012-01-01

    The purpose of this study was to examine the effect of a Toll-like receptor 5 (TLR5) agonist, CBLB502, on the growth and radiosensitivity of A549 lung cancer cells in vivo. Expression of myeloid differentiation factor 88 (MyD88) or TLR5 was stably knocked down in human lung cancer cells (A549) using lentivirus expressing short hairpin RNA targeting human MyD88 or TLR5. Lack of MyD88 or TLR5 expression enhanced tumor growth in mouse xenografts of A549 lung cancer cells. CBLB502 inhibited the growth of A549 lung cancer cells, not A549-MyD88-KD cells in vivo in the murine xenograft model. Our results showed that the inhibition of A549 by CBLB502 in vivo was realized through regulating the expression of neutrophil recruiting cytokines and neutrophil infiltration. Finally, we found that activation of TLR5 signaling did not affect the radiosensitivity of tumors in vivo.

  16. Pain management in lung cancer.

    PubMed

    Nurwidya, Fariz; Syahruddin, Elisna; Yunus, Faisal

    2016-01-01

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

  17. In vitro invasion of small-cell lung cancer cell lines correlates with expression of epidermal growth factor receptor.

    PubMed Central

    Damstrup, L.; Rude Voldborg, B.; Spang-Thomsen, M.; Brünner, N.; Skovgaard Poulsen, H.

    1998-01-01

    Formation of metastasis is a multistep process involving attachment to the basement membrane, local proteolysis and migration into surrounding tissues, lymph or bloodstream. In the present study, we have analysed the correlation between in vitro invasion and presence of the epidermal growth factor receptor (EGFR) in a panel of 21 small-cell lung cancer (SCLC) cell lines. We have previously reported that ten of these cell lines expressed EGFR protein detected by radioreceptor and affinity labelling assays. In 11 small-cell lung cancer (SCLC) cell lines, EGFR mRNA was detected by Northern blot analysis. In vitro invasion in a Boyden chamber assay was found in all EGFR-positive cell lines, whereas no invasion was detected in the EGFR-negative cell lines. Quantification of the in vitro invasion in 12 selected SCLC cell lines demonstrated that, in the EGFR-positive cell lines, between 5% and 16% of the cells added to the upper chamber were able to traverse the Matrigel membrane. Expression of several matrix metalloproteases (MMP), of tissue inhibitor of MMP (TIMP) and of cathepsin B was evaluated by immunoprecipitation, Western blot analysis and reverse transcriptase polymerase chain reaction (RT-PCR). However, in vitro invasive SCLC cell lines could not be distinguished from non-invasive cell lines based on the expression pattern of these molecules. In six SCLC cell lines, in vitro invasion was also determined in the presence of the EGFR-neutralizing monoclonal antibody mAb528. The addition of this antibody resulted in a significant reduction of the in vitro invasion in three selected EGFR-positive cell lines. Our results show that only EGFR-positive SCLC cell lines had the in vitro invasive phenotype, and it is therefore suggested that the EGFR might play an important role for the invasion potential of SCLC cell lines. Images Figure 1 Figure 3 Figure 4 PMID:9744504

  18. Enhanced suppression of tumor growth by concomitant treatment of human lung cancer cells with suberoylanilide hydroxamic acid and arsenic trioxide

    SciTech Connect

    Chien, Chia-Wen; Yao, Ju-Hsien; Chang, Shih-Yu; Lee, Pei-Chih; Lee, Te-Chang

    2011-11-15

    The efficacy of arsenic trioxide (ATO) against acute promyelocytic leukemia (APL) and relapsed APL has been well documented. ATO may cause DNA damage by generating reactive oxygen intermediates. Suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, modulates gene and protein expression via histone-dependent or -independent pathways that may result in chromatin decondensation, cell cycle arrest, differentiation, and apoptosis. We investigated whether ATO and SAHA act synergistically to enhance the death of cancer cells. Our current findings showed that combined treatment with ATO and SAHA resulted in enhanced suppression of non-small-cell lung carcinoma in vitro in H1299 cells and in vivo in a xenograft mouse model. Flow cytometric analysis of annexin V+ cells showed that apoptotic cell death was significantly enhanced after combined treatment with ATO and SAHA. At the doses used, ATO did not interfere with cell cycle progression, but SAHA induced p21 expression and led to G1 arrest. A Comet assay demonstrated that ATO, but not SAHA, induced DNA strand breaks in H1299 cells; however, co-treatment with SAHA significantly increased ATO-induced DNA damage. Moreover, SAHA enhanced acetylation of histone H3 and sensitized genomic DNA to DNase I digestion. Our results suggest that SAHA may cause chromatin relaxation and increase cellular susceptibility to ATO-induced DNA damage. Combined administration of SAHA and ATO may be an effective approach to the treatment of lung cancer. -- Highlights: Black-Right-Pointing-Pointer ATO and SAHA are therapeutic agents with different action modes. Black-Right-Pointing-Pointer Combination of ATO and SAHA synergistically inhibits tumor cell growth. Black-Right-Pointing-Pointer SAHA loosens chromatin structure resulting in increased sensitivity to DNase I. Black-Right-Pointing-Pointer ATO-induced DNA damage and apoptosis are enhanced by co-treatment with SAHA.

  19. Clinical definition of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer.

    PubMed

    Jackman, David; Pao, William; Riely, Gregory J; Engelman, Jeffrey A; Kris, Mark G; Jänne, Pasi A; Lynch, Thomas; Johnson, Bruce E; Miller, Vincent A

    2010-01-10

    Ten percent of North American patients with non-small-cell lung cancer have tumors with somatic mutations in the gene for the epidermal growth factor receptor (EGFR). Approximately 70% of patients whose lung cancers harbor somatic mutations in exons encoding the tyrosine kinase domain of EGFR experience significant tumor regressions when treated with the EGFR tyrosine kinase inhibitors (TKIs) gefitinib or erlotinib. However, the overwhelming majority of these patients inevitably acquire resistance to either drug. Currently, the clinical definition of such secondary or acquired resistance is not clear. We propose the following criteria be used to define more precisely acquired resistance to EGFR TKIs. All patients should have the following criteria: previous treatment with a single-agent EGFR TKI (eg, gefitinib or erlotinib); either or both of the following: a tumor that harbors an EGFR mutation known to be associated with drug sensitivity or objective clinical benefit from treatment with an EGFR TKI; systemic progression of disease (Response Evaluation Criteria in Solid Tumors [RECIST] or WHO) while on continuous treatment with gefitinib or erlotinib within the last 30 days; and no intervening systemic therapy between cessation of gefitinib or erlotinib and initiation of new therapy. The relatively simple definition proposed here will lead to a more uniform approach to investigating the problem of acquired resistance to EGFR TKIs in this unique patient population. These guidelines should minimize reporting of false-positive and false-negative activity in these clinical trials and would facilitate the identification of agents that truly overcome acquired resistance to gefitinib and erlotinib.

  20. Palliative care in lung cancer.

    PubMed

    Ferrell, Betty; Koczywas, Marianna; Grannis, Fred; Harrington, Annie

    2011-04-01

    Advancements in the surgical and medical treatment of lung cancer have resulted in more favorable short-term survival outcomes. After initial treatment, lung cancer requires continued surveillance and follow-up for long-term side effects and possible recurrence. The integration of quality palliative care into routine clinical care of patients with lung cancer after surgical intervention is essential in preserving function and optimizing quality of life through survivorship. An interdisciplinary palliative care model can effectively link patients to the appropriate supportive care services in a timely fashion. This article describes the role of palliative care for patients with lung cancer.

  1. Small molecular peptide-ScFv αvβ3 conjugates specifically inhibit lung cancer cell growth in vitro and in vivo

    PubMed Central

    Qiu, Qianqian; Wang, Qiongyao; Deng, Changxu; Sun, Yanqin; Chen, Taoliang; Guo, Linlang; Zhang, Fan

    2016-01-01

    Integrin αvβ3 (ITG) is highly expressed in various cancers and is considered a major target for anti-angiogensis cancer therapy. The single chain fragment variable of which (ScFv αvβ3) has been reported to inhibit tumor growth both in vitro and in vivo. Here, we conjugated cdGIGPQc which can exclusively bind to NSCLC cells according to our previous study synthesized by SPPS with ScFv αvβ3 expressed in E. coli BL21 (DE3) to develop a novel lung cancer specific targeted drug. Specific cell targeting of cdGIGPQc-ScFv was assessed in parallel with the single ScFv and a control nonspecific peptide-ScFv through immunofluorescence and flow cytometry while the αvβ3-binding property was examined by Western blot. Our results showed that cdGIGPQc-ScFv retained both the lung cancer-binding activity of cdGIGPQc and the antigen-recognizing ability of ScFv αvβ3 in vitro. CCK8 assays and in animal experiments suggested that cdGIGPQc-ScFv possessed a superior antitumor effect than ScFv and nonspecific peptide-ScFv both in vitro and vivo. Further immunohistochemical staining revealed that cdGIGPQc-ScFv retarded lung cancer growth through inhibiting tumor angiogensis and proliferation. Therefore, cdGIGPQc delivery of ScFv αvβ3 to lung cancer may be a hopeful new strategy for enhancing specific antitumor efficacy and cdGIGPQc-ScFv could be a potential drug for lung cancer targeted treatment. PMID:28042504

  2. Erythromycin and clarithromycin modulation of growth factor-induced expression of heparanase mRNA on human lung cancer cells in vitro.

    PubMed Central

    Sasaki, M; Ito, T; Kashima, M; Fukui, S; Izumiyama, N; Watanabe, A; Sano, M; Fujiwara, Y; Miura, M

    2001-01-01

    Heparanase activity is correlated with the metastatic potential of several cancer cells and is a key enzyme in the breakdown of tissue barriers. It is also involved in the regulation of growth factor and cytokine activity. However, little is known about the factors that induce heparanase in cancer cells. We investigated the effect of three growth factors, platelet-derived growth factor (PDGF), hepatocyte growth factor (HGF) and basic fibroblast growth factor (bFGF), on heparanase mRNA induction in lung cancer cells in vitro. In addition, we examined the effect of erythromycin (EM) and clarithromycin (CAM), which are 14-membered ring macrolide antibiotics that act as biological response modifiers, on the expression of heparanase mRNA induced by growth factors. PDGF, HGF and bFGF stimulated cell migration activity and enhanced the expression of heparanase mRNA in the human lung adenocarcinoma cell line A549. Via different mechanisms, EM and CAM modulate the induction by these factors of heparanase mRNA expression on A549 cells. EM also significantly suppressed A549 cell migration induced by PDGF and HGF, and CAM significantly suppressed A549cell migration induced by bFGF. The results suggest that the growth factors PDGF, HGF and bFGF are important inducers of heparanase in potentially invasive and metastatic cancer cells. The suppressive effect of heparanase mRNA expression by EM and CAM may have interestingtherapeutic applications in the prevention of metastasis. PMID:11759110

  3. Growth status significantly affects the response of human lung cancer cells to antitumor polyamine-analogue exposure.

    PubMed

    Carlisle, Diane L; Devereux, Wendy L; Hacker, Amy; Woster, Patrick M; Casero, Robert A

    2002-08-01

    Human solid tumors frequently have a relatively small growth fraction,which interferes with the action of many chemotherapeutic agents that target actively cycling cells. Several polyamine analogues are currently being developed for clinical application against human solid tumors including N1,N11-bis(ethyl)norspermine. Therefore, an effort was made to examine the effects of growth rate on polyamine-analogue efficacy. Low growth fraction (LGF) cell cultures of the human non-small cell lung cancer cell line NCI-H157 were generated to partially mimic solid tumors with low mitotic indices. Log-phase cells were compared with LGF cells with respect to cell survival and biochemical effects after exposure to polyamine analogues. The results demonstrate generally that LGF NCI-H157 cells were sensitive to analogue treatment. However, the dose necessary to elicit a response in LGF cells was an order of magnitude higher than the dose needed in log-phase cells. Additionally, the biochemical effects of analogues were similar between log phase and LGF cells with regard to a down-regulation of polyamine biosynthesis as measured by ornithine decarboxylase activity and an increase in polyamine catabolism as indicated by an increase in spermidine/spermine N1-acetyltransferase activity. However, biochemical effects were less dramatic in the LGF cells than those observed in the log-phase cells. The overall results of these studies suggest that the growth status of solid tumors can significantly affect the response to antitumor polyamine analogues, and growth fraction must be considered in the continued development and use of the polyamine analogues.

  4. Optimizing the use of epidermal growth factor receptor inhibitors in advanced non-small-lung cancer (NSCLC)

    PubMed Central

    Shash, Emad; Peccatori, Fedro Alessandro; Azim, Hatem A

    2011-01-01

    Lung cancer is the leading cause of cancer-related death in US and Europe. Treatment with a platinum-based chemotherapy remains the standard of care, however with modest effect on quality of life and overall survival which seldom reaches 1 year. Recently, several classes of targeted agents have emerged showing promising results. In particular, agents targeting the epidermal growth factor receptor (EGFR) showed impressive clinical activity both in the first line and salvage settings. However, it is evident that these drugs are not effective in all patients. Putting into consideration the very high cost of these agents, there is an urgent need to provide reliable tools to identify those patients that would derive the maximum benefit from these drugs. Several predictive biomarkers were developed to identify those patients who would derive the maximal benefit of these drugs. In this review we will discuss the recent updates on the role of EGFR inhibitors in the treatment of advanced NSCLC and the role of predictive bio-markers in patient selection. PMID:22263061

  5. Expression of nerve growth factor and hypoxia inducible factor-1α and its correlation with angiogenesis in non-small cell lung cancer.

    PubMed

    Lu, Qing-li; Liu, Jian; Zhu, Xiao-li; Xu, Wen-jia

    2014-06-01

    In order to investigate the expression of nerve growth factor (NGF) and hypoxia inducible factor-1α (HIF-1α) and its correlation with angiogenesis in non-small cell lung cancer (NSCLC), paraffin-embedded tissue blocks from 20 patients with NSCLC were examined. Twenty corresponding para-cancerous lung tissue specimens were obtained to serve as a control. The expression of NGF, HIF-1α, and vascular endothelial growth factor (VEGF) in the NSCLC tissues was detected by using immunohistochemistry. The microvascular density (MVD) was determined by CD31 staining. The results showed that the expression levels of NGF, HIF-1α and VEGF in the NSCLC tissues were remarkably higher than those in the para-cancerous lung tissues (P<0.05). There was significant difference in the MVD between the NSCLC tissues (9.19±1.43) and para-cancerous lung tissues (2.23±1.19) (P<0.05). There were positive correlations between NGF and VEGF, between HIF-1α and VEGF, and between NGF and HIF-1α in NSCLC tissues, with the spearman correlation coefficient being 0.588, 0.519 and 0.588, respectively. In NSCLC tissues, the MVD had a positive correlation with the three factors (P<0.05). Theses results suggest that NGF and HIF-1α are synergically involved in the angiogenesis of NSCLC.

  6. American Cancer Society Lung Cancer Screening Guidelines

    PubMed Central

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

    2013-01-01

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

  7. American Cancer Society lung cancer screening guidelines.

    PubMed

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

    2013-01-01

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

  8. Blocking M2 muscarinic receptor signaling inhibits tumor growth and reverses epithelial-mesenchymal transition (EMT) in non-small cell lung cancer (NSCLC).

    PubMed

    Zhao, Qingnan; Gu, Xiajing; Zhang, Chun; Lu, Qin; Chen, Hongzhuan; Xu, Lu

    2015-01-01

    Lung cancers express non-neuronal, cholinergic autoparacrine loop, which facilitates tumor growth. Interruption of M3 muscarinic cholinergic signaling has been reported to inhibit small cell lung cancer (SCLC) growth. The purpose of this study is to investigate if blocking autoparacrine muscarinic cholinergic signaling could inhibit non-small cell lung cancer (NSCLC) growth and possible underlying mechanisms. Our results showed that PC9 and A549 cells expressed all 5 subtypes of muscarinic receptor (mAChR) and blocking M2 mAChR (M2R) signaling using selective antagonist methoctramine or short hairpin RNA (shRNA) inhibited tumor cell proliferation in vitro and in vivo. Consistent with AChR agonists stimulating p44/42 MAPK (Erk1/2) and Akt phosphorylation, blocking M2R signaling decreased MAPK and Akt phosphorylation, indicating that non-neuronal ACh functions as an autoparacrine growth factor signaling in part through activation of M2R and downstream MAPK and Akt pathways. Importantly, further studies revealed that blocking M2R signaling also reversed epithelial-mesenchymal transition (EMT) in vitro and in vivo, indicating that non-neuronal ACh promotes EMT partially through activation of M2R. These findings demonstrate that M2R plays a role in the growth and progression of NSCLC and suggest M2R antagonists may be an efficacious adjuvant therapy for NSCLC.

  9. Drugs Approved for Lung Cancer

    Cancer.gov

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

  10. Fibroblast growth factor signaling and inhibition in non-small cell lung cancer and their role in squamous cell tumors

    PubMed Central

    Salgia, Ravi

    2014-01-01

    With the introduction of targeted agents primarily applicable to non-small cell lung cancer (NSCLC) of adenocarcinoma histology, there is a heightened unmet need in the squamous cell carcinoma population. Targeting the angiogenic fibroblast growth factor (FGF)/FGF receptor (FGFR) signaling pathway is among the strategies being explored in squamous NSCLC; these efforts are supported by growth-promoting effects of FGF signaling in preclinical studies (including interactions with other pathways) and observations suggesting that FGF/FGFR-related aberrations may be more common in squamous versus adenocarcinoma and other histologies. A number of different anti-FGF/FGFR approaches have shown promise in preclinical studies. Clinical trials of two multitargeted tyrosine kinase inhibitors are restricting enrollment to patients with squamous NSCLC: a phase I/II trial of nintedanib added to first-line gemcitabine/cisplatin and a phase II trial of ponatinib for previously treated advanced disease, with the latter requiring not only squamous disease but also a confirmed FGFR kinase amplification or mutation. There are several ongoing clinical trials of multitargeted agents in general NSCLC populations, including but not limited to patients with squamous disease. Other FGF/FGFR-targeted agents are in earlier clinical development. While results are awaited from these clinical investigations in squamous NSCLC and other disease settings, additional research is needed to elucidate the role of FGF/FGFR signaling in the biology of NSCLC of different histologies. PMID:24711160

  11. Effect of macrophage-modulating agents on in vivo growth of transplantable Lewis lung cancer in mice.

    PubMed

    Nowicki, A; Ostrowska, G; Aukerman, S L; Wiktor-Jedrzejczak, W

    1994-01-01

    C57Bl/6 mice, bearing transplantable Lewis lung cancer (non-metastatic subline) implanted either subcutaneously or intraperitoneally were treated with macrophage colony stimulating factor (M-CSF, 10(6) units per mouse, per day for 19 days), Escherichia coli lipopolysaccharide or both. Lipopolysaccharide (5 micrograms per mouse) administered daily once a day for up to 30 days impaired both subcutaneous and intraperitoneal tumor growth and prolonged survival of tumor bearing mice. Macrophage colony stimulating factor, administered daily, inhibited only subcutaneous tumor growth, both when administered alone and in combination with with lipopolysaccharide, and had no effect on intraperitoneal tumor. Moreover, it did not prolong survival of tumor bearing mice, when administered alone, and nullified the effects of lipopolysaccharide when administered concomitantly. These data suggest that macrophage colony stimulating factor, at least in this tumor model and in this dose schedule, offers little benefit. In contrast, the present data confirm earlier suggestions on therapeutic usefulness of bacterial lipopolysaccharide in neoplastic disease, which makes this compound an interesting candidate for future clinical trials.

  12. Physical activity and lung cancer prevention.

    PubMed

    Emaus, Aina; Thune, Inger

    2011-01-01

    Since lung cancer is among the cancers with the highest incidence and has the highest mortality rate of cancer worldwide, the means of reducing its impact are urgently needed. Emerging evidence shows that physical activity plays an etiological role in lung cancer risk reduction. The majority of studies support the fact that total and recreational physical activity reduces lung cancer risk by 20-30% for women and 20-50% for men, and there is evidence of a dose-response effect. The biological mechanisms operating between physical activity and lung cancer are likely complex and influenced by many factors including inherited or acquired susceptibility genes, gender, smoking, and other environmental factors. Several plausible biological factors and mechanisms have been hypothesized linking physical activity to reduced lung cancer risk including: improved pulmonary function, reduced concentrations of carcinogenic agents in the lungs, enhanced immune function, reduced inflammation, enhanced DNA repair capacity, changes in growth factor levels and possible gene-physical activity interactions. Future research should target the possible subgroup effects and the biologic mechanisms that may be involved.

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

    PubMed

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

    2015-08-01

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

  14. Dexamethasone suppresses the growth of human non-small cell lung cancer via inducing estrogen sulfotransferase and inactivating estrogen

    PubMed Central

    Wang, Li-jie; Li, Jian; Hao, Fang-ran; Yuan, Yin; Li, Jing-yun; Lu, Wei; Zhou, Tian-yan

    2016-01-01

    Aim: Dexamethasone (DEX) is a widely used synthetic glucocorticoid, which has shown anti-cancer efficacy and anti-estrogenic activity. In this study we explored the possibility that DEX might be used as an endocrine therapeutic agent to treat human non-small cell lung cancer (NSCLC). Methods: The viability and proliferation of human NSCLC cell lines A549 and H1299 were assessed in vitro. Anti-tumor action was also evaluated in A549 xenograft nude mice treated with DEX (2 or 4 mg·kg−1·d−1, ig) or the positive control tamoxifen (50 mg·kg−1·d−1, ig) for 32 d. The expression of estrogen sulfotransferase (EST) in tumor cells and tissues was examined. The intratumoral estrogen levels and uterine estrogen responses were measured. Results: DEX displayed mild cytotoxicity to the NSCLC cells (IC50 >500 μmol/L) compared to tamoxifen (IC50 <50 μmol/L), but it was able to inhibit the cell proliferation at low micromolar ranges. Furthermore, DEX (0.1–10 μmol/L) dose-dependently up-regulated EST expression in the cells, and inhibited the cell migration in vitro. Triclosan, a sulfation inhibitor, was able to diminish DEX-caused inhibition on the cell viability. In A549 xenograft nude mice, DEX or tamoxifen administration remarkably suppressed the tumor growth. Moreover, DEX administration dose-dependently increased EST expression in tumor tissues, and reduced intratumoral estrogen levels as well as the volumes and weights of uterine. Conclusion: DEX suppresses the growth of A549 xenograft tumors via inducing EST and decreasing estradiol levels in tumor tissues, suggesting that DEX may be used as anti-estrogenic agent for the treatment of NSCLC. PMID:27133297

  15. [Asbestos-related lung cancer].

    PubMed

    Lotti, M

    2010-01-01

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

  16. Expression Levels of Some Antioxidant and Epidermal Growth Factor Receptor Genes in Patients with Early-Stage Non-Small Cell Lung Cancer

    PubMed Central

    De Palma, Giuseppe; Mozzoni, Paola; Acampa, Olga; Internullo, Eveline; Carbognani, Paolo; Rusca, Michele; Goldoni, Matteo; Corradi, Massimo; Tiseo, Marcello; Apostoli, Pietro; Mutti, Antonio

    2010-01-01

    This study was aimed at: (i) investigating the expression profiles of some antioxidant and epidermal growth factor receptor genes in cancerous and unaffected tissues of patients undergoing lung resection for non-small cell lung cancer (NSCLC) (cross-sectional phase), (ii) evaluating if gene expression levels at the time of surgery may be associated to patients' survival (prospective phase). Antioxidant genes included heme oxygenase 1 (HO-1), superoxide dismutase-1 (SOD-1), and -2 (SOD-2), whereas epidermal growth factor receptor genes consisted of epidermal growth factor receptor (EGFR) and v-erb-b2 erythroblastic leukaemia viral oncogene homolog 2 (HER-2). Twenty-eight couples of lung biopsies were obtained and gene transcripts were quantified by Real Time RT-PCR. The average follow-up of patients lasted about 60 months. In the cancerous tissues, antioxidant genes were significantly hypo-expressed than in unaffected tissues. The HER-2 transcript levels prevailed in adenocarcinomas, whereas EGFR in squamocellular carcinomas. Patients overexpressing HER-2 in the cancerous tissues showed significantly lower 5-year survival than the others. PMID:20700416

  17. LUNG CANCER AND PULMONARY THROMBOEMBOLISM

    PubMed Central

    Cukic, Vesna; Ustamujic, Aida

    2015-01-01

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

  18. Not all epidermal growth factor receptor mutations in lung cancer are created equal: Perspectives for individualized treatment strategy.

    PubMed

    Kobayashi, Yoshihisa; Mitsudomi, Tetsuya

    2016-09-01

    Somatic mutations in the epidermal growth factor receptor (EGFR) gene are present in approximately 20% (in Caucasians) to 40% (in East Asians) of adenocarcinomas of the lung. Targeted therapy for these lung cancers has been established based on evidence regarding mainly common mutations; that is, exon 19 deletions (Del19) and L858R. EGFR-tyrosine kinase inhibitors (TKI), gefitinib, erlotinib or afatinib showed high objective response rates (ORR) of approximately 60%. Several studies suggested that Del19 might be more sensitive to EGFR-TKI than L858R. On the other hand, it has been difficult to establish evidence for other less common mutations, accounting for 12% of all EGFR mutations, because there are many variants and many studies have excluded patients with these uncommon mutations. However, recent studies revealed that these rare genotypes could be targetable if appropriate TKI are selected. For example, G719X (X denotes A, S, C and so on), Del18, E709K, insertions in exon 19 (Ins19), S768I or L861Q showed moderate sensitivities to gefitinib or erlotinb with ORR of 30%-50%. However, afatinib appeared to be especially effective for these tumors. Although Ins20s (except for insFQEA) have been regarded as resistant mutations, osimertinib may be effective for rare subtypes of them and nazartinib (EGF816) is promising for the majority of them. For the further development of targeted therapy in all EGFR mutations, it is important to precisely detect targetable mutations, to select the most appropriate TKI for each mutation, and to continue investigating in vitro studies and collecting clinical data on even rare mutations.

  19. Expression of pleiotrophin in small cell lung cancer.

    PubMed

    Wang, H Q; Wang, J

    2015-01-01

    Pleiotrophin (PTN) is a kind of heparin binding growth factor closely related to tumor progression. This study aimed to discuss the significance of the expression of PTN in benign and malignant lung cancer tissues, especially small cell lung cancer. Lung cancer samples were collected for study and lung tissue samples with benign lesions were taken as controls. The expression of PTN was detected using tissue chip combined with the immunohistochemical method, and the differences of small cell lung cancer with non-small cell lung cancer and benign lesion tissue were compared. It was found that PTN expression was mainly located in the cytoplasm and membrane of cells; PTN expression in the lung cancer group was higher than that in the control group (p < 0.01), and PTN expression in the small cell cancer group was higher than that in the squamous carcinoma group and glandular cancer group (p < 0.05). In addition, PTN expression quantity in patients with lung cancer were in close correlation with TNM staging, pathological type and tumor differentiation degree (p < 0.05). PTN was found to express abnormally high in lung cancer, especially small cell lung cancer tissue. PTN is most likely to be a new tumor marker for diagnosis and prognosis of lung cancer.

  20. Association between survivin genetic polymorphisms and epidermal growth factor receptor mutation in non-small-cell lung cancer

    PubMed Central

    Liu, Tu-Chen; Hsieh, Ming-Ju; Wu, Wen-Jun; Chou, Ying-Erh; Chiang, Whei-Ling; Yang, Shun-Fa; Su, Shih-Chi; Tsao, Thomas Chang-Yao

    2016-01-01

    Survivin is an anti-apoptotic protein that is implicated in the regulation of apoptosis and cell cycle in various types of cancers. The current study explored the effect of survivin gene polymorphisms and EGFR mutations in non-small-cell lung carcinoma (NSCLC) patients. A total of 360 participants, including 291 adenocarcinoma lung cancer and 69 squamous cell carcinoma lung cancer patients, were selected for the analysis of three survivin genetic variants (survivin -31, +9194, and +9809) by using real-time PCR genotyping. The results indicated that GC+CC genotypes of survivin -31 were significant association with EGFR mutation in lung adenocarcinoma patients (adjusted odds ratio=3.498, 95% CI = 1.171-10.448; p<0.01). Moreover, The GC+CC genotypes of survivin -31 were associated with EGFR L858R mutation but not in exon 19 in-frame deletions. Furthermore, among patients in exon 19 in-frame deletions, those who have at least one polymorphic G allele of survivin -31 have an increased incidence to develop late-stage when compared with those patients homozygous for C/C (OR, 4.800; 95% CI, 1.305-17.658). In conclusion, our results showed that survivin genetic variants were related to EGFR mutation in lung adenocarcinoma patients and might contribute to pathological development to NSCLC. PMID:27994498

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

    PubMed Central

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

    2016-01-01

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

  2. Polonium and Lung Cancer

    PubMed Central

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

    2011-01-01

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

  3. Expression and autoregulation of transforming growth factor beta receptor mRNA in small-cell lung cancer cell lines.

    PubMed Central

    Nørgaard, P.; Spang-Thomsen, M.; Poulsen, H. S.

    1996-01-01

    In small-cell lung cancer cell lines resistance to growth inhibition by transforming growth factor (TGF)-beta 1, was previously shown to correlate with lack of TGF-beta receptor I (RI) and II (RII) proteins. To further investigate the role of these receptors, the expression of mRNA for RI, RII and beta-glycan (RIII) was examined. The results showed that loss of RII mRNA correlated with TGF-beta 1 resistance. In contrast, RI-and beta-glycan mRNA was expressed by all cell lines, including those lacking expression of these proteins. According to Southern blot analysis, the loss of type II mRNA was not due to gross structural changes in the gene. The effect of TGF-beta 1 on expression of TGF-beta receptor mRNA (receptor autoregulation) was examined by quantitative Northern blotting in four cell lines with different expression of TGF-beta receptor proteins. In two cell lines expressing all three TGF-beta receptor proteins beta-glycan mRNA was rapidly down-regulated and this effect was sustained throughout the 24 h observation period. RI and RII mRNAs were slightly increased 24 h after treatment. In one cell line sensitive to growth inhibition by TGF-beta, 1 but lacking beta-glycan expression, and one cell line expressing only beta-glycan and thus TGF-beta 1 -resistant, no autoregulation of mRNA of either TGF-beta receptor was demonstrated. The results suggest that TGF-beta 1 regulates the expression of its receptors, in particular beta-glycan, and that this effect is dependent on co-expression of beta-glycan, RI and RII. Images Figure 1 Figure 2 Figure 4 PMID:8624260

  4. CCL21/CCR7 up-regulate vascular endothelial growth factor-D expression via ERK pathway in human non-small cell lung cancer cells.

    PubMed

    Sun, Limei; Zhang, Qingfu; Li, Yang; Tang, Na; Qiu, Xueshan

    2015-01-01

    Lymphangiogenesis has received considerable attention and become a new research hotspot of tumor metastasis. Recently, C-C chemokine receptor 7 (CCR7) is known to promote metastasis of non-small cell lung cancer (NSCLC) cells into lymph nodes. In this study, we investigated the relationship between CCL21/CCR7 and the lymphangiogenic factor vascular endothelial growth factor (VEGF)-D in human lung cancer cells and its impact on patients' prognosis. We found that CCL21/CCR7 increase the expression of VEGF-D in NSCLC Cell Lines through induced ERK1/2 and Akt phosphorylation. In addition, our study found that the expression levels of CCR7 and CCL21 were correlated with VEGF-D, lymphatic vessels density (LVD), clinical stages, lymph node metastasis, and patient Survival in 90 human non-small cell lung cancer (NSCLC) specimens. Taken together, our results provide evidence that CCL21/CCR7 induce VEGF-D up-regulation and promote lymphangiogenesis via ERK/Akt pathway in lung cancer.

  5. Targeting SALL4 by entinostat in lung cancer

    PubMed Central

    Hong, Clarice Kit Yee; Zhao, Wenxiu; Wang, Fei; Tatetsu, Hiro; Yan, Benedict; Qi, Lihua; Fletcher, Jonathan A.; Yang, Henry; Soo, Ross

    2016-01-01

    The overall survival of lung cancer patients remains dismal despite the availability of targeted therapies. Oncofetal protein SALL4 is a novel cancer target. We herein report that SALL4 was aberrantly expressed in a subset of lung cancer patients with poor survival. SALL4 silencing by RNA interference or SALL4 peptide inhibitor treatment led to impaired lung cancer cell growth. Expression profiling of SALL4-knockdown cells demonstrated that both the EGFR and IGF1R signaling pathways were affected. Connectivity Map analysis revealed the HDAC inhibitor entinostat as a potential drug in treating SALL4-expressing cancers, and this was confirmed in 17 lung cancer cell lines. In summary, we report for the first time that entinostat can target SALL4-positive lung cancer. This lays the foundation for future clinical studies evaluating the therapeutic efficacy of entinostat in SALL4-positive lung cancer patients. PMID:27705911

  6. Tyrosine kinase inhibitors for epidermal growth factor receptor gene mutation-positive non-small cell lung cancers: an update for recent advances in therapeutics.

    PubMed

    Chung, Clement

    2016-06-01

    The presence of activating gene mutations in the epidermal growth factor receptor of non-small cell lung cancer patients is predictive (improved progression-free survival and improved response rate) when treated with small molecule tyrosine kinase inhibitors such as gefitinib, erlotinib and afatinib. The two most common mutations that account for greater than 85% of all EGFR gene mutations are in-frame deletions in exon 19 (LREA deletions) and substitution in exon 21 (L858R). Exon 18 mutations occur much less frequently at about 4% of all EGFR gene mutations. Together, exon 19 deletion and exon 21 L858R gene substitution are present in about 10% of Caucasian patients and 20-40% of Asian patients with non-small cell lung cancer. T790M gene mutation at exon 20 is associated with acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors. Early studies showed that activating EGFR gene mutations are most common in patients with adenocarcinoma histology, women, never smokers and those of Asian ethnicity. A recent multi-center phase III trial suggested that frontline epidermal growth factor receptor tyrosine kinase inhibitor therapy with afatinib is associated with improved progression-free survival compared to chemotherapy regardless of race. Moreover, guidelines now suggest EGFR gene mutation testing should be conducted in all patients with lung adenocarcinoma or mixed lung cancers with an adenocarcinoma component, regardless of characteristics such as smoking status, gender or race. The success of targeted therapies in non-small cell lung cancer patients has changed the treatment paradigm in metastatic non-small cell lung cancer. However, despite a durable response of greater than a year, resistance to epidermal growth factor receptor tyrosine kinase inhibitors inevitably occurs. This mini-review describes the clinically relevant EGFR gene mutations and the efficacy/toxicity of small molecule epidermal growth factor receptor tyrosine kinase

  7. Epidermal Growth Factor Receptor targeting in non-small cell lung cancer: revisiting different strategies against the same target.

    PubMed

    Castañón, Eduardo; Martín, Patricia; Rolfo, Christian; Fusco, Juan P; Ceniceros, Lucía; Legaspi, Jairo; Santisteban, Marta; Gil-Bazo, Ignacio

    2014-01-01

    Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitors (TKIs) have changed the paradigm of treatment in non-small cell lung cancer (NSCLC). The molecular biology study of EGFR has led to clinical trials that select patients more accurately, regarding the presence of EGFR activating mutations. Nonetheless, a lack of response or a temporary condition of the response has been detected in patients on EGFR TKIs. This has urged to study potential resistance mechanisms underneath. The most important ones are the presence of secondary mutations in EGFR, such as T790M, or the overexpression of mesenchymal-epithelial transition factor (MET) that may explain why patients who initially respond to EGFR TKIs, may ultimately become refractory. Several approaches have been taken and new drugs both targeting EGFR resistance-mutation or MET are currently being developed. Here we review and update the EGFR biological pathway as well as the clinical data leading to approval of the EGFR TKIs currently in the market. New compounds under investigation targeting resistance mutations or dually targeting EGFR and other relevant receptors are also reviewed and discussed.

  8. Osimertinib for the Treatment of Metastatic Epidermal Growth Factor T970M Positive Non-Small Cell Lung Cancer.

    PubMed

    Khozin, Sean; Weinstock, Chana; Blumenthal, Gideon M; Cheng, Joyce; He, Kun; Zhuang, Luning; Zhao, Hong; Orbach, Rosane Charlab; Fan, Ingrid; Keegan, Patricia; Pazdur, Richard

    2016-12-06

    On November 13, 2015, FDA granted accelerated approval to osimertinib (TAGRISSO™; AstraZeneca), a breakthrough therapy-designated drug for the treatment of patients with metastatic epidermal growth factor receptor (EGFR) T790M-positive non-small cell lung cancer (NSCLC), as detected by an FDA-approved test, with progression on or after EGFR tyrosine kinase inhibitor therapy. Approval was based on durable tumor response rates in two single-arm, multicenter trials: the dose extension cohort of a first-in-human trial (AURA extension; n=201) and a fixed-dose, activity-estimating trial (AURA2; n=210). Osimertinib was administered at 80 mg orally once daily. The objective response rates (ORR) per blinded independent committee review were 57% (95% CI: 50%, 64%) in AURA extension and 61% (95% CI: 54%, 68%) in AURA2. Median duration of response (DOR) could not be estimated. Supportive efficacy data from 63 patients in the dose-finding part of the FIH trial demonstrated ORR of 51% (95% CI: 38%, 64%) with median DOR of 12.4 months. Common adverse events (AEs) evaluated in 411 patients included diarrhea (42%), rash (41%), dry skin (31%), and nail toxicity (25%). Grade 3-4 AEs occurred in 28% of patients and 6% discontinued treatment due to AEs.

  9. Discovery of 2'-hydroxychalcones as autophagy inducer in A549 lung cancer cells.

    PubMed

    Wang, Fang-Wu; Wang, Sheng-Qing; Zhao, Bao-Xiang; Miao, Jun-Ying

    2014-05-21

    A series of 2'-hydroxychalcone derivatives was synthesized and the effects of all the compounds on growth of A549 lung cancer cell were investigated. The results showed that all compounds had inhibitory effects on the growth of A549 lung cancer cells and compound possessed the highest growth inhibitory effect and induced autophagy of A549 lung cancer cells.

  10. Fibroblast-led cancer cell invasion is activated by epithelial-mesenchymal transition through platelet-derived growth factor BB secretion of lung adenocarcinoma.

    PubMed

    Neri, Shinya; Miyashita, Tomoyuki; Hashimoto, Hiroko; Suda, Yoshitaka; Ishibashi, Masayuki; Kii, Hiroaki; Watanabe, Hirotada; Kuwata, Takeshi; Tsuboi, Masahiro; Goto, Koichi; Menju, Toshi; Sonobe, Makoto; Date, Hiroshi; Ochiai, Atsushi; Ishii, Genichiro

    2017-06-01

    Cancer-associated fibroblast (CAF)-dependent local invasion is the process by which cancer cells invade the extracellular matrix using tracks that have been physically remodeled by CAFs. In the present study, we investigated the process by which the epithelial-mesenchymal transition (EMT) of cancer cells affect CAF-dependent local invasion. Using an in vitro collagen invasion assay, we showed cancer cells undergoing EMT to promote the matrix-remodeling ability of CAFs and thereby enhance CAF-dependent local cancer cell invasion. Platelet-derived growth factor (PDGF)-BB secretion was significantly elevated in cancer cells undergoing EMT, and this induced an increase in the invasion ability of both CAFs and cancer cells. Conversely, knockdown of PDGF-B expression in cancer cells undergoing EMT, or treatment with a PDGF-receptor inhibitor, decreased the invasion ability of both CAFs and cancer cells. By analyzing the gene expression profiles of 442 patients with lung adenocarcinomas, we established that high expression of PDGF-B and presentation of mesenchymal-like tumors were significantly associated with a high rate of disease recurrence and poor patient prognosis. Thus, cancer cells undergoing EMT may accelerate their own ability to invade local tissues via PDGF-BB secretion to promote CAF matrix remodeling. Therefore, targeting PDGF signaling between cancer cells undergoing EMT and CAFs is a promising therapeutic target to inhibit cancer progression and improve patient prognosis.

  11. LOXL4 knockdown enhances tumor growth and lung metastasis through collagen-dependent extracellular matrix changes in triple-negative breast cancer.

    PubMed

    Choi, Sul Ki; Kim, Hoe Suk; Jin, Tiefeng; Moon, Woo Kyung

    2017-01-02

    Lysyl oxidase (LOX) family genes catalyze collagen cross-link formation. To determine the effects of lysyl oxidase-like 4 (LOXL4) expression on breast tumor formation and metastasis, we evaluated primary tumor growth and lung metastasis in mice injected with LOXL4-knockdown MDA-MB-231 triple-negative human breast cancer cells. In addition, we analyzed overall survival in breast cancer patients based on LOXL4 expression using a public online database. In the mouse xenograft model, LOXL4 knockdown increased primary tumor growth and lung colonization as well as collagen I and IV, lysine hydroxylase 1 and 2, and prolyl 4-hydroxylase subunit alpha 1 and 2 levels. Second harmonic generation imaging revealed that LOXL4 knockdown resulted in the thickening of collagen bundles within tumors. In addition, weak LOXL4 expression was associated with poor overall survival in breast cancer patients from the BreastMark dataset, and this association was strongest in triple-negative breast cancer patients. These results demonstrate that weak LOXL4 expression leads to remodeling of the extracellular matrix through induction of collagen synthesis, deposition, and structural changes. These alterations in turn promote tumor growth and metastasis and are associated with poor clinical outcomes in triple-negative breast cancer.

  12. Epidermal growth factor activates telomerase activity by direct binding of Ets-2 to hTERT promoter in lung cancer cells.

    PubMed

    Hsu, Chung-Ping; Lee, Li-Wen; Tang, Sheau-Chung; Hsin, I-Lun; Lin, Yu-Wen; Ko, Jiunn-Liang

    2015-07-01

    Growth signals are directly or indirectly involved in telomerase regulation. In this study, we investigated molecular mechanisms of the effect of EGF (epidermal growth factor) on regulating hTERT (human telomerase reverse transcriptase) expression. To elucidate specific transcription factors involved in EGF-stimulated hTERT transcription in A549 and H1299 lung cancer cells, transcription factors drives hTERT promoter activity, such as Myc, Mad, and Ets-2, was evaluated on luciferase reporter assay. The upregulation of hTERT promoter by Ets-2 and Myc were abolished by Mad. Using DAPA (DNA affinity precipitation assay), Ets-2 binding to SNP (T) was stronger than Ets-2 binding to SNP (C) at -245 bp upstream of the transcription start site within the core promoter of hTERT. Ets-2 silence by siRNA decreased hTERT expression at mRNA and protein levels. The regulation of hTERT promoter by EGF/Ets-2 was diminished via the EGFR kinase signal pathway-specific inhibitors AG1478 and Iressa. Inhibitors of Erk and Akt inhibited Ets-2-activated hTERT promoter activity. These data suggested that Ets-2, a genuine cancer-specific transcription factor, is actively involved in EGFR kinase-induced hTERT overexpression pathway in lung cancer cells. Blockage of this pathway may contribute to targeted gene therapy in lung cancer.

  13. Amphiregulin triggered epidermal growth factor receptor activation confers in vivo crizotinib-resistance of EML4-ALK lung cancer and circumvention by epidermal growth factor receptor inhibitors.

    PubMed

    Taniguchi, Hirokazu; Takeuchi, Shinji; Fukuda, Koji; Nakagawa, Takayuki; Arai, Sachiko; Nanjo, Shigeki; Yamada, Tadaaki; Yamaguchi, Hiroyuki; Mukae, Hiroshi; Yano, Seiji

    2017-01-01

    Crizotinib, a first-generation anaplastic lymphoma kinase (ALK) tyrosine-kinase inhibitor, is known to be effective against echinoderm microtubule-associated protein-like 4 (EML4)-ALK-positive non-small cell lung cancers. Nonetheless, the tumors subsequently become resistant to crizotinib and recur in almost every case. The mechanism of the acquired resistance needs to be deciphered. In this study, we established crizotinib-resistant cells (A925LPE3-CR) via long-term administration of crizotinib to a mouse model of pleural carcinomatous effusions; this model involved implantation of the A925LPE3 cell line, which harbors the EML4-ALK gene rearrangement. The resistant cells did not have the secondary ALK mutations frequently occurring in crizotinib-resistant cells, and these cells were cross-resistant to alectinib and ceritinib as well. In cell clone #2, which is one of the clones of A925LPE3-CR, crizotinib sensitivity was restored via the inhibition of epidermal growth factor receptor (EGFR) by means of an EGFR tyrosine-kinase inhibitor (erlotinib) or an anti-EGFR antibody (cetuximab) in vitro and in the murine xenograft model. Cell clone #2 did not have an EGFR mutation, but the expression of amphiregulin (AREG), one of EGFR ligands, was significantly increased. A knockdown of AREG with small interfering RNAs restored the sensitivity to crizotinib. These data suggest that overexpression of EGFR ligands such as AREG can cause resistance to crizotinib, and that inhibition of EGFR signaling may be a promising strategy to overcome crizotinib resistance in EML4-ALK lung cancer.

  14. LUNG CANCER IN NEVER SMOKERS: MOLECULAR PROFILES AND THERAPEUTIC IMPLICATIONS

    PubMed Central

    Rudin, Charles M.; Avila-Tang, Erika; Harris, Curtis C.; Herman, James G.; Hirsch, Fred R.; Pao, William; Schwartz, Ann G.; Vahakangas, Kirsi H.; Samet, Jonathan M.

    2010-01-01

    The majority of lung cancers are caused by long term exposure to the several classes of carcinogens present in tobacco smoke. While a significant fraction of lung cancers in never smokers may also be attributable to tobacco, many such cancers arise in the absence of detectable tobacco exposure, and may follow a very different cellular and molecular pathway of malignant transformation. Recent studies summarized here suggest that lung cancers arising in never smokers have a distinct natural history, profile of oncogenic mutations, and response to targeted therapy. The majority of molecular analyses of lung cancer have focused on genetic profiling of pathways responsible for metabolism of primary tobacco carcinogens. Limited research has been conducted evaluating familial aggregation and genetic linkage of lung cancer, particularly among never smokers in whom such associations might be expected to be strongest. Data emerging over the past several years demonstrates that lung cancers in never smokers are much more likely to carry activating mutations of the Epidermal Growth Factor Receptor (EGFR), a key oncogenic factor and direct therapeutic target of several newer anti-cancer drugs. EGFR mutant lung cancers may represent a distinct class of lung cancers, enriched in the never smoking population, and less clearly linked to direct tobacco carcinogenesis. These insights followed initial testing and demonstration of efficacy of EGFR-targeted drugs. Focused analysis of molecular carcinogenesis in lung cancers in never smokers is needed, and may provide additional biologic insight with therapeutic implications for lung cancers in both ever smokers and never smokers. PMID:19755392

  15. Safety, immunogenicity and preliminary efficacy of multiple-site vaccination with an Epidermal Growth Factor (EGF) based cancer vaccine in advanced non small cell lung cancer (NSCLC) patients

    PubMed Central

    2011-01-01

    The prognosis of patients with advanced non small cell lung (NSCLC) cancer remains dismal. Epidermal Growth Factor Receptor is over-expressed in many epithelial derived tumors and its role in the development and progression of NSCLC is widely documented. CimaVax-EGF is a therapeutic cancer vaccine composed by human recombinant Epidermal Growth Factor (EGF) conjugated to a carrier protein, P64K from Neisseria Meningitides. The vaccine is intended to induce antibodies against self EGF that would block EGF-EGFR interaction. CimaVax-EGF has been evaluated so far in more than 1000 advanced NSCLC patients, as second line therapy. Two separate studies were compared to assess the impact of high dose vaccination at multiple anatomic sites in terms of immunogenicity, safety and preliminary efficacy in stage IIIb/IV NSCLC patients. In both clinical trials, patients started vaccination 1 month after finishing first line chemotherapy. Vaccination at 4 sites with 2.4 mg of EGF (high dose) was very safe. The most frequent adverse events were grade 1 or 2 injection site reactions, fever, headache and vomiting. Patients had a trend toward higher antibody response. The percent of very good responders significantly augmented and there was a faster decrease of circulating EGF. All vaccinated patients and those classified as good responders immunized with high dose at 4 sites, had a large tendency to improved survival. PMID:22024351

  16. Occupational exposure and lung cancer

    PubMed Central

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

    2013-01-01

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

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

    PubMed Central

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

    2011-01-01

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

  18. Complete remission through icotinib treatment in Non-small cell lung cancer epidermal growth factor receptor mutation patient with brain metastasis: A case report

    PubMed Central

    Wang, Tao; Wang, Ruimin; Dong, Zhouhuan; Liang, Naichao

    2016-01-01

    Abstract Brain metastasis (BM) has been universally recognized as a poor prognostic factor in non-small cell lung cancer (NSCLC). Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have shown efficacy in treating BM with an EGFR mutation. This paper reports a case of BM patient with EGFR-mutated NSCLC. According to the findings, a complete remission (CR) of the BM was achieved by icotinib treatment without conducting a radiotherapy, which was followed by a resection of the primary lung cancer lesion and lymph nodes. After one-year follow-up, the disease progressed to liver metastasis and liver lesion biopsy showed a T790M mutation. The patient responded well to the combination treatment of AZD9291 and icotinib after the failure of transcatheter arterial chemoembolization (TACE). This case report suggests that icotinib has a sustainable anticancer response to BM and the combination with icotinib and AZD9291 is effective for liver metastasis with T790M.

  19. Small RNA combination therapy for lung cancer.

    PubMed

    Xue, Wen; Dahlman, James E; Tammela, Tuomas; Khan, Omar F; Sood, Sabina; Dave, Apeksha; Cai, Wenxin; Chirino, Leilani M; Yang, Gillian R; Bronson, Roderick; Crowley, Denise G; Sahay, Gaurav; Schroeder, Avi; Langer, Robert; Anderson, Daniel G; Jacks, Tyler

    2014-08-26

    MicroRNAs (miRNAs) and siRNAs have enormous potential as cancer therapeutics, but their effective delivery to most solid tumors has been difficult. Here, we show that a new lung-targeting nanoparticle is capable of delivering miRNA mimics and siRNAs to lung adenocarcinoma cells in vitro and to tumors in a genetically engineered mouse model of lung cancer based on activation of oncogenic Kirsten rat sarcoma viral oncogene homolog (Kras) and loss of p53 function. Therapeutic delivery of miR-34a, a p53-regulated tumor suppressor miRNA, restored miR-34a levels in lung tumors, specifically down-regulated miR-34a target genes, and slowed tumor growth. The delivery of siRNAs targeting Kras reduced Kras gene expression and MAPK signaling, increased apoptosis, and inhibited tumor growth. The combination of miR-34a and siRNA targeting Kras improved therapeutic responses over those observed with either small RNA alone, leading to tumor regression. Furthermore, nanoparticle-mediated small RNA delivery plus conventional, cisplatin-based chemotherapy prolonged survival in this model compared with chemotherapy alone. These findings demonstrate that RNA combination therapy is possible in an autochthonous model of lung cancer and provide preclinical support for the use of small RNA therapies in patients who have cancer.

  20. Lung cancer and tobacco smoking.

    PubMed

    Boyle, P; Maisonneuve, P

    1995-06-01

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

  1. Impact of Pretreatment Tumor Growth Rate on Outcome of Early-Stage Lung Cancer Treated With Stereotactic Body Radiation Therapy

    SciTech Connect

    Atallah, Soha; Cho, B.C. John; Allibhai, Zishan; Taremi, Mojgan; Giuliani, Meredith; Le, Lisa W.; Brade, Anthony; Sun, Alexander; Bezjak, Andrea; Hope, Andrew J.

    2014-07-01

    Purpose: To determine the influence of pretreatment tumor growth rate on outcomes in patients with early-stage non-small cell lung cancer (NSCLC) treated with stereotactic body radiation therapy (SBRT). Methods and Materials: A review was conducted on 160 patients with T1-T2N0M0 NSCLC treated with SBRT at single institution. The patient's demographic and clinical data, time interval (t) between diagnostic and planning computed tomography (CT), vital status, disease status, and cause of death were extracted from a prospectively kept database. Differences in gross tumor volume between diagnostic CT (GTV1) and planning CT (GTV2) were recorded, and growth rate was calculated by use of specific growth rate (SGR). Kaplan-Meier curves were constructed for overall survival (OS). Differences between groups were compared with a log-rank test. Multivariate analyses were performed by use of the Cox proportional hazard model with SGR and other relevant clinical factors. Cumulative incidence was calculated for local, regional, and distant failures by use of the competing risk approach and was compared with Gray's test. Results: The median time interval between diagnostic and planning CT was 82 days. The patients were divided into 2 groups, and the median SGR was used as a cut-off. The median survival times were 38.6 and 27.7 months for the low and high SGR groups, respectively (P=.03). Eastern Cooperative Oncology Group performance status (P=.01), sex (P=.04), SGR (P=.03), and GTV2 (P=.002) were predictive for OS in multivariable Cox regression analysis and, except sex, were similarly predictive for failure-free survival (FFS). The 3-year cumulative incidences of regional failure were 19.2% and 6.0% for the high and low SGR groups, respectively (P=.047). Conclusion: High SGR was correlated with both poorer OS and FFS in patients with early-stage NSCLC treated with SBRT. If validated, this measurement may be useful in identifying patients most likely to benefit from adjuvant

  2. Early detection of COPD is important for lung cancer surveillance.

    PubMed

    Sekine, Yasuo; Katsura, Hideki; Koh, Eitetsu; Hiroshima, Kenzo; Fujisawa, Takehiko

    2012-05-01

    It is well known that chronic obstructive pulmonary disease (COPD) is a significant risk factor for lung cancer. Approximately 1% of COPD patients develop lung cancer every year, which may be associated with genetic susceptibility to cigarette smoke. Chronic inflammation caused by toxic gases can induce COPD and lung cancer. Inflammatory mediators may promote the growth of bronchioalveolar stem cells, and activation of nuclear factor-κB and signal transducer and activator of transcription 3 play crucial roles in the development of lung cancer from COPD. Low-dose computed tomography (LDCT) is an effective procedure for the early detection of lung cancer in high-risk patients. However, determining which patients should be screened for lung cancer in a primary care setting is difficult. In this article, we review the epidemiology and aetiology of lung cancer associated with COPD, verify the efficacy of lung cancer screening by LDCT, and discuss the importance of early detection of COPD for lung cancer surveillance. We propose that, for the prevention of both diseases, COPD screening in smokers should be initiated as early as possible, so they can stop smoking and so that candidates for an efficient lung cancer screening programme can be identified.

  3. Is it feasible to detect epidermal growth factor receptor mutations in circulating tumor cells in nonsmall cell lung cancer?

    PubMed Central

    Liu, Yafang; Xing, Ze; Zhan, Ping; Liu, Hongbing; Ye, Wei; Lv, Tangfeng; Song, Yong

    2016-01-01

    Abstract Background: The value of circulating tumor cells (CTCs) in detecting epidermal growth factor receptor (EGFR) mutations in patients with nonsmall cell lung cancer (NSCLC) is controversial. We performed a meta-analysis to investigate the diagnostic significance of CTCs with tumor tissues as the standard control. Methods: A systematic literature search, including papers published until November 26, 2015, was performed using PubMed, Medline, Embase, Web of Science, and the China National Knowledge Infrastructure, and the references of retrieved articles were screened. The pooled sensitivity, specificity, and diagnostic odds ratio (DOR) were calculated according to the data selection from the included studies. The evaluation indexes of the diagnostic performance were the summary receiver operating characteristic curve (SROC) and area under the SROC (AUSROC). Results: Eight eligible articles with a total of 170 participants were identified in our meta-analysis. The pooled sensitivity and specificity were 0.91 [95% CI: 0.55–0.99] and 0.99 [95% CI: 0.59–1.00]. The positive likelihood ratio and negative likelihood ratio were 68 [95% CI: 1.4–3364] and 0.09 [95% CI: 0.01–0.64], respectively. The DOR was 788 [95% CI: 9–71884]. The high diagnostic performance of CTCs in detecting EGFR mutations was indicated by the AUSROC of 0.99 [95% CI: 0.98–1.00]. Conclusions: CTCs are a feasible and highly specific biomarker for detecting the EGFR mutation status in NSCLC patients. PMID:27893656

  4. Intercalated chemotherapy and erlotinib for non-small cell lung cancer (NSCLC) with activating epidermal growth factor receptor (EGFR) mutations

    PubMed Central

    Zwitter, Matjaz; Rajer, Mirjana; Stanic, Karmen; Vrankar, Martina; Doma, Andrej; Cuderman, Anka; Grmek, Marko; Kern, Izidor; Kovac, Viljem

    2016-01-01

    ABSTRACT Among attempts to delay development of resistance to tyrosine kinase inhibitors (TKIs) in patients with advanced non-small cell lung cancer (NSCLC) with activating mutations of epidermal growth factor receptor (EGFR), intercalated therapy has not been properly evaluated. In a phase II trial, 38 patients with EGFR mutated NSCLC in advanced stage were treated with 4 to 6 3-weekly cycles of intercalated schedule with gemcitabine (1250 mg/m2, days 1 and 4), cisplatin (75 mg/m2, day 2) and erlotinib (150 mg, days 5 – 15), followed by continuous erlotinib as maintenance. In addition to standard radiologic evaluation according to RECIST, PET/CT was done prior to treatment and at 6 months, using PERCIST as a method for assessment of response. The primary endpoint was progression-free survival (PFS). In general, tolerance to treatment was good, even among 8 patients with performance status 2–3 and 13 patients with brain metastases; grade 4 toxicity included 2 cases of neutropenia and 4 thrombo-embolic events. Complete response (CR) or partial response (PR) were seen in 15 (39.5%) and 17 (44.7%) cases, respectively. All cases of CR were confirmed also by PET/CT. Median PFS was 23.4 months and median overall survival (OS) was 38.3  months. After a median follow-up of 35 months, 8 patients are still in CR and on maintenance erlotinib. In conclusion, intercalated treatment for treatment-naive patients with EGFR activating mutations leads to excellent response rate and prolonged PFS and survival. Comparison of the intercalated schedule to monotherapy with TKIs in a randomized trial is warranted. PMID:27261103

  5. Structural, biochemical, and clinical characterization of epidermal growth factor receptor (EGFR) exon 20 insertion mutations in lung cancer.

    PubMed

    Yasuda, Hiroyuki; Park, Eunyoung; Yun, Cai-Hong; Sng, Natasha J; Lucena-Araujo, Antonio R; Yeo, Wee-Lee; Huberman, Mark S; Cohen, David W; Nakayama, Sohei; Ishioka, Kota; Yamaguchi, Norihiro; Hanna, Megan; Oxnard, Geoffrey R; Lathan, Christopher S; Moran, Teresa; Sequist, Lecia V; Chaft, Jamie E; Riely, Gregory J; Arcila, Maria E; Soo, Ross A; Meyerson, Matthew; Eck, Michael J; Kobayashi, Susumu S; Costa, Daniel B

    2013-12-18

    Epidermal growth factor receptor (EGFR) gene mutations (G719X, exon 19 deletions/insertions, L858R, and L861Q) predict favorable responses to EGFR tyrosine kinase inhibitors (TKIs) in advanced non-small cell lung cancer (NSCLC). However, EGFR exon 20 insertion mutations (~10% of all EGFR mutations) are generally associated with insensitivity to available TKIs (gefitinib, erlotinib, and afatinib). The basis of this primary resistance is poorly understood. We studied a broad subset of exon 20 insertion mutations, comparing in vitro TKI sensitivity with responses to gefitinib and erlotinib in NSCLC patients, and found that most are resistant to EGFR TKIs. The crystal structure of a representative TKI-insensitive mutant (D770_N771insNPG) reveals an unaltered adenosine triphosphate-binding pocket, and the inserted residues form a wedge at the end of the C helix that promotes the active kinase conformation. Unlike EGFR-L858R, D770_N771insNPG activates EGFR without increasing its affinity for EGFR TKIs. Unexpectedly, we find that EGFR-A763_Y764insFQEA is highly sensitive to EGFR TKIs in vitro, and patients whose NSCLCs harbor this mutation respond to erlotinib. Analysis of the A763_Y764insFQEA mutant indicates that the inserted residues shift the register of the C helix in the N-terminal direction, altering the structure in the region that is also affected by the TKI-sensitive EGFR-L858R. Our studies reveal intricate differences between EGFR mutations, their biology, and their response to EGFR TKIs.

  6. Evaluation of the Role of Invadopodia in Lung Cancer Cell Growth and Invasion

    DTIC Science & Technology

    2014-11-01

    attach to the assay cover slips. Two of the cell lines (H1792 and H1650) were judged to be the best at forming invadopodia. Infect NCI- H460 with...that the H460 cells would in fact not be a good choice for the assays, and we therefore did not perform these experiments. Months 4-6 Test control...and Tks5 knockdown NCI- H460 cells in in vitro assays of invasion and 3D growth. See above for why we chose not to work with this cell line

  7. Lung cancer: the immune system and radiation.

    PubMed

    Mendes, F; Antunes, C; Abrantes, A M; Gonçalves, A C; Nobre-Gois, I; Sarmento, A B; Botelho, M F; Rosa, M S

    2015-01-01

    Lung cancer has a known relationship with smoking and is one of the leading causes of cancer-related death worldwide. Although the number of studies discussing lung cancer is vast, treatment efficacy is still suboptimal due to the wide range of factors that affect patient outcome. This review aims to collect information on lung cancer treatment, specially focused on radiation therapy. It also compiles information regarding the influence of radiotherapy on the immune system and its response to tumour cells. It evaluates how immune cells react after radiation exposure and the influence of their cytokines in the tumour microenvironment. The literature analysis points out that the immune system is a very promising field of investigation regarding prognosis, mostly because the stromal microenvironment in the tumour can provide some information about what can succeed in the future concerning treatment choices and perspectives. T cells (CD4+ and CD8+), interleukin-8, vascular endothelial growth factor and transforming growth factor-β seem to have a key role in the immune response after radiation exposure. The lack of large scale studies means there is no common consensus in the scientific community about the role of the immune system in lung cancer patients treated with radiotherapy. Clarification of the mechanism behind the immune response after radiation can lead to better treatments and better quality life for patients.

  8. Vascular endothelial growth factor directly stimulates tumour cell proliferation in non-small cell lung cancer.

    PubMed

    Devery, Aoife M; Wadekar, Rekha; Bokobza, Sivan M; Weber, Anika M; Jiang, Yanyan; Ryan, Anderson J

    2015-09-01

    Vascular endothelial growth factor (VEGF) is a key stimulator of physiological and pathological angiogenesis. VEGF signals primarily through VEGF receptor 2 (VEGFR2), a receptor tyrosine kinase whose expression is found predominantly on endothelial cells. The purpose of this study was to determine the role of VEGFR2 expression in NSCLC cells. NSCLC cells and tissue sections were stained for VEGFR2 expression by immunohistochemistry (IHC). Immunoblotting and ELISA were used to determine the activation and inhibition of VEGFR2 and its downstream signalling pathways. Five-day proliferation assays were carried out in the presence or absence of VEGF. IHC analysis of NSCLC demonstrated tumour cell VEGFR2 expression in 20% of samples. Immunoblot analysis showed expression of VEGFR2 protein in 3/8 NSCLC cell lines that correlated with VEGFR2 mRNA expression levels. VEGF-dependent VEGFR2 activation was apparent in NSCLC cells, and was associated with increased tumor cell proliferation. Cediranib treatment or siRNA against VEGFR2 inhibited VEGF-dependent increases in cell proliferation. Inhibition of VEGFR2 tyrosine kinase activity using cediranib was more effective than inhibition of AKT (MK2206) or MEK (AZD6244) for overcoming VEGFR2-driven cell proliferation. VEGF treatment did not affect cell survival following treatment with radiation, cisplatin, docetaxel or gemcitabine. Our data suggest that a subset of NSCLC tumour cells express functional VEGFR2 which can act to promote VEGF-dependent tumour cell growth. In this tumour subset, therapies targeting VEGFR2 signalling, such as cediranib, have the potential to inhibit both tumour cell proliferation and angiogenesis.

  9. Early detection of lung cancer

    PubMed Central

    Midthun, David E.

    2016-01-01

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

  10. Lung Cancer Risk Prediction Models

    Cancer.gov

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

  11. Carotenoids and lung cancer prevention

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  12. Inhibition of acetyl-CoA carboxylase suppresses fatty acid synthesis and tumor growth of non-small cell lung cancer in preclinical models

    PubMed Central

    Svensson, Robert U.; Parker, Seth J.; Eichner, Lillian J.; Kolar, Matthew J.; Wallace, Martina; Brun, Sonja N.; Lombardo, Portia S.; Van Nostrand, Jeanine L.; Hutchins, Amanda; Vera, Lilliana; Gerken, Laurie; Greenwood, Jeremy; Bhat, Sathesh; Harriman, Geraldine; Westlin, William F.; Harwood, H. James; Saghatelian, Alan; Kapeller, Rosana; Metallo, Christian M.; Shaw, Reuben J.

    2016-01-01

    Continuous de novo fatty acid synthesis is a common feature of cancer required to meet the biosynthetic demands of a growing tumor. This process is controlled by the rate-limiting enzyme acetyl-CoA carboxylase (ACC), an attractive but traditionally intractable drug target. Here, we provide genetic and pharmacological evidence that in preclinical models ACC is required to maintain de novo fatty acid synthesis needed for growth and viability of non-small cell lung cancer (NSCLC). We describe the ability of ND-646—an allosteric inhibitor of the ACC enzymes ACC1 and ACC2 that prevents ACC subunit dimerization—to suppress fatty acid synthesis in vitro and in vivo. Chronic ND-646 treatment of xenograft and genetically engineered mouse models of NSCLC inhibited tumor growth. When administered as a single agent or in combination with the standard-of-care drug carboplatin, ND-646 markedly suppressed lung tumor growth in the Kras;Trp53−/− (also known as KRAS p53) and Kras;Stk11−/− (also known as KRAS Lkb1) mouse models of NSCLC. These findings demonstrate that ACC mediates a metabolic liability of NSCLC and that ACC inhibition by ND-646 is detrimental to NSCLC growth, supporting further examination of the use of ACC inhibitors in oncology. PMID:27643638

  13. Inhibitory Effects of Salinomycin on Cell Survival, Colony Growth, Migration, and Invasion of Human Non-Small Cell Lung Cancer A549 and LNM35: Involvement of NAG-1.

    PubMed

    Arafat, Kholoud; Iratni, Rabah; Takahashi, Takashi; Parekh, Khatija; Al Dhaheri, Yusra; Adrian, Thomas E; Attoub, Samir

    2013-01-01

    A major challenge for oncologists and pharmacologists is to develop more potent and less toxic drugs that will decrease the tumor growth and improve the survival of lung cancer patients. Salinomycin is a polyether antibiotic used to kill gram-positive bacteria including mycobacteria, protozoans such as plasmodium falciparum, and the parasites responsible for the poultry disease coccidiosis. This old agent is now a serious anti-cancer drug candidate that selectively inhibits the growth of cancer stem cells. We investigated the impact of salinomycin on survival, colony growth, migration and invasion of the differentiated human non-small cell lung cancer lines LNM35 and A549. Salinomycin caused concentration- and time-dependent reduction in viability of LNM35 and A549 cells through a caspase 3/7-associated cell death pathway. Similarly, salinomycin (2.5-5 µM for 7 days) significantly decreased the growth of LNM35 and A549 colonies in soft agar. Metastasis is the main cause of death related to lung cancer. In this context, salinomycin induced a time- and concentration-dependent inhibition of cell migration and invasion. We also demonstrated for the first time that salinomycin induced a marked increase in the expression of the pro-apoptotic protein NAG-1 leading to the inhibition of lung cancer cell invasion but not cell survival. These findings identify salinomycin as a promising novel therapeutic agent for lung cancer.

  14. Cigarette smoke and lung cancer

    SciTech Connect

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

    1987-01-01

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

  15. Functional imaging in lung cancer

    PubMed Central

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

    2014-01-01

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

  16. Drug Resistance to EGFR Inhibitors in Lung Cancer | Office of Cancer Genomics

    Cancer.gov

    The discovery of mutations in epidermal growth factor receptor (EGFR) has dramatically changed the treatment of patients with non-small-cell lung cancer (NSCLC), the leading cause of cancer deaths worldwide.

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

    ClinicalTrials.gov

    2016-04-19

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

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

    ClinicalTrials.gov

    2016-02-18

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

  19. FGFR Signaling as a Target for Lung Cancer Therapy.

    PubMed

    Desai, Arpita; Adjei, Alex A

    2016-01-01

    Lung cancer is the leading cause of cancer-related death in developed countries. Recently, molecular targeted therapies have shown promising results in the management of lung cancer. These therapies require a clear understanding of the relevant pathways that drive carcinogenesis and maintenance of the malignant phenotype. The fibroblast growth factor receptor (FGFR) signaling axis is one such pathway that plays a central role in normal cellular function. Alterations in this pathway have been found in many cancers. In this review article, we focus on the role of this pathway in lung cancer. We present the molecular structure of FGFR, the interaction of the receptor with its ligands (the fibroblast growth factors), its downstream signaling, and aberrations in the FGFR pathway. We also discuss clinical trials involving selective and multikinase FGFR inhibitors in lung cancer treatment.

  20. Risk Profiling May Improve Lung Cancer Screening

    Cancer.gov

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

  1. Tobacco Smoking and Lung Cancer

    PubMed Central

    Furrukh, Muhammad

    2013-01-01

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

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

    PubMed Central

    Sethi, T.

    1997-01-01

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

  3. MicroRNA-1304 suppresses human non-small cell lung cancer cell growth in vitro by targeting heme oxygenase-1

    PubMed Central

    Li, Cheng-gang; Pu, Meng-fan; Li, Chun-zhu; Gao, Man; Liu, Ming-xia; Yu, Cun-zhi; Yan, Hong; Peng, Chun; Zhao, Yang; Li, Yu; Ma, Ze-long; Qi, Xin-ming; Wang, Yi-zheng; Miao, Ling-ling; Ren, Jin

    2017-01-01

    Previous studies have shown that microRNA-1304 (miR-1304) is dysregulated in certain types of cancers, including non-small cell lung cancer (NSCLC), and might be involved in tumor survival and/or growth. In this study we investigated the direct target of miR-1304 and its function in NSCLC in vitro. Human lung adenocarcinoma cell lines (A549 and NCI-H1975) were studied. The cell proliferation and survival were investigated via cell counting, MTT and colony-formation assays. Cell apoptosis and cell cycle were examined using annexin V-PE/7-AAD and PI staining assays, respectively. The dual-luciferase reporter assay was used to verify post-transcriptional regulation of heme oxygenase-1 (HO-1) by miR-1304. CRISPR/Cas9 was used to deplete endogenous miR-1304. Overexpression of MiR-1304 significantly decreased the number and viability of NSCLC cells and colony formation, and induced cell apoptosis and G0/G1 phase cell cycle arrest. HO-1 was demonstrated to be a direct target of miR-1304 in NSCLC cells. Restoration of HO-1 expression by hemin (20 μmol/L) abolished the inhibition of miR-1304 on cell growth and rescued miR-1304-induced apoptosis in A549 cells. Suppression of endogenous miR-1304 with anti-1304 significantly increased HO-1 expression and promoted cell growth and survival in A549 cells. In 17 human NSCLC tissue samples, miR-1304 expression was significantly decreased, while HO-1 expression was significantly increased as compared to normal lung tissues. MicroRNA-1304 is a tumor suppressor and HO-1 is its direct target in NSCLC. The results suggest the potential for miR-1304 as a therapeutic target for NSCLC. PMID:27641735

  4. p53 status is a major determinant of effects of decreasing peroxiredoxin I expression on tumor growth and response of lung cancer cells to treatment

    SciTech Connect

    Chen, M.-F. . E-mail: miaofen@adm.cgmh.org.tw; Chen, W.-C.; Wu, C.-T.; Lin, P.-Y.; Shau Hungyi; Liao, S.-K.; Yang, C.-T.; Lee, K.-D.

    2006-12-01

    Purpose: The potential roles of peroxiredoxin (Prx) I in carcinogenesis and treatment have been explored. Our previous study revealed differences between A549 (functional p53) and H1299 (null p53) Prx I antisense transfectants. The discrepancy might have resulted from the p53 status. In this study, we further investigated the role of Prx I and p53 on lung cancer growth and the response to treatment in vitro and in vivo. Methods: We established stable A549 and H1299 transfectants with Prx I antisense and p53, respectively. We then examined their characteristics in vitro and used nude mice xenografts of these cell lines to compare their capacity for tumor invasion and spontaneous metastasis and their sensitivity to radiotherapy. Results: Increased reactive oxygen species caused by lower Prx I activity induced p53 expression. In lethal stress, the augmentation of reactive oxygen species was partially reversed by blocking p53 in A549 with Prx I antisense. We demonstrated the potential contribution of p53-dependent mechanisms to inhibit lung tumor growth and increase radiosensitization using H1299 transfected with p53 in vitro and in vivo. An increased p53 level attenuated the capacity of the cells for metastasis by decreasing vascular endothelial growth factor and induced radiosensitization by increased apoptosis and cell senescence and by regulating intracellular reactive oxygen species. Conclusion: These results suggest that p53 status has an important role in the tumor-inhibiting and radiosensitizing effects of decreasing Prx I. Both Prx I and p53 may be powerful prognosticators for lung cancer.

  5. Biomarkers of erlotinib response in non-small cell lung cancer tumors that do not harbor the more common epidermal growth factor receptor mutations

    PubMed Central

    López-Ayllón, Blanca D; de Castro-Carpeño, Javier; Rodriguez, Carlos; Pernía, Olga; de Cáceres, Inmaculada Ibañez; Belda-Iniesta, Cristobal; Perona, Rosario; Sastre, Leandro

    2015-01-01

    Non-small cell lung cancer (NSCLC) represents approximately 85% of all lung cancers, which are the leading cause of cancer-related deaths in the world. Tyrosine kinase inhibitors such as erlotinib represent one therapeutic options presently recommended for tumors produced by activating mutations in the gene coding of epidermal growth factor receptor (EGFR). The aim of this study is the identification of possible biomarkers for tumor sensitivity to erlotinib in the absence of the main EGFR mutations. The erlotinib sensitivity of cells isolated from 41 untreated NSCLC patients was determined and compared with the presence of the more frequent EGFR mutations. Several patients had tumor cells highly sensitive to erlitinib in the absence of the EGFR mutations analyzed. The gene expression profile of 3 erlotinib-sensitive tumors was compared with that of 4 resistant tumors by DNA microarray hybridization. Sixteen genes were expressed at significantly higher levels in the resistant tumors than in the sensitive tumors. The possible correlation between erlotinib sensitivity and the expression of these genes was further analyzed using the data for the NSCLC, breast cancer and colon cancer cell lines of the NCI60 collection. The expression of these genes was correlated with the overall survival of 5 patients treated with erlotinib, according to The Cancer Genome Atlas (TCGA) database. Overlapping groups of 7, 5 and 3 genes, including UGT1A6, TRIB3, MET, MMP7, COL17A1, LCN2 and PTPRZ1, whose expression correlated with erlotinib activity was identified. In particular, low MET expression levels showed the strongest correlation. PMID:26045797

  6. Lung Cancer Screening

    MedlinePlus

    ... medical care even if there are symptoms. False-positive test results can occur. Screening test results may ... even though no cancer is present. A false-positive test result (one that shows there is cancer ...

  7. Overexpression of microRNA‑125a‑3p effectively inhibits the cell growth and invasion of lung cancer cells by regulating the mouse double minute 2 homolog/p53 signaling pathway.

    PubMed

    Li, Shenglei; Li, Xin; Zhao, Huasi; Gao, Ming; Wang, Feng; Li, Wencai

    2015-10-01

    MicroRNAs (miRs) are a family of small non-coding RNAs that are 21‑24 nucleotides in length. Decreased expression of hsa‑miR‑125a‑3p is observed in a number of patients with non‑small cell lung cancer; however, it is not clear how this miRNA regulates the growth and invasion of lung tumor cells. The aim of the present study was to identify the function of hsa‑miR‑125a‑3p in the growth and invasion of lung cancer cells. The expression of hsa‑miR‑125a‑3p in the A549, NCI‑H460 and SPCA‑1 lung cancer cell lines was analyzed by reverse transcription‑quantitative polymerase chain reaction and the human bronchiolar epithelium cell line (HBE) was used as a control. The results demonstrated that the expression of hsa‑miR‑125a‑3p was significantly lower in NCI‑H460, A549 and SPCA‑1 cells, compared with that in HBE cells. Overexpression of sense miR‑125a‑3p in the A549 lung cancer cell line inhibited cell proliferation for 5‑7 days (P<0.01), and transfection of antisense miR‑125a‑3p did not suppress the cell growth of the lung cancer cells. In addition, overexpression of miR‑125a‑3p in the NCI‑H460 lung cancer cell line markedly induced cell apoptosis, which was detected by fluorescence‑activated cell sorting with annexin V‑fluorescein isothiocyanate/propidium iodide staining. The results of the Transwell migration assay also revealed that transfection of miR‑125a‑3p resulted in decreased migration of lung cancer tumor cells. The pro‑apoptotic gene p53 expression was detected by western blot analysis. The results revealed that the expression of mouse double minute (MDM)‑2 homolog, the principal cellular antagonist of p53, was decreased and p53 expression was upregulated in sense has‑miR‑125a‑3p transfected A549 cells. This was consistent with that observed in NCI‑H460 cells, suggesting that hsa‑miR‑125a‑3p may be involved in the regulation of the MDM2/p53 signaling pathway in lung cancer cells. In

  8. [Advances of molecular targeted therapy in squamous cell lung cancer].

    PubMed

    Ma, Li; Zhang, Shucai

    2013-12-01

    Squamous cell lung cancer (SQCLC) is one of the most prevalent subtypes of lung cancer worldwide, about 400,000 persons die from squamous-cell lung cancer around the world, and its pathogenesis is closely linked with tobacco exposure. Unfortunately, squamous-cell lung cancer patients do not benefit from major advances in the development of targeted therapeutics such as epidermal growth factor receptor (EGFR) inhibitors or anaplastic lymphoma kinase (ALK) inhibitors that show exquisite activity in lung adenocarcinomas with EGFR mutations or echinoderm microtubule associated protein like-4 (EML4)-ALK fusions, respectively. Major efforts have been launched to characterize the genomes of squamous-cell lung cancers. Among the new results emanating from these efforts are amplifications of the fibroblast growth factor receptor 1 (FGFR1) gene, the discoidin domain receptor 2 (DDR2) gene mutation as potential novel targets for the treatment of SQCLCs. Researchers find that there are many specific molecular targeted genes in the genome of squamous-cell lung cancer patients. These changes play a vital role in cell cycle regulation, oxidative stress, cell apoptosis, squamous epithelium differentiation, may be the candidate targeted moleculars in SQCLCs. Here, we provide a review on these discoveries and their implications for clinical trials in squamous-cell lung cancer assessing the value of novel therapeutics addressing these targets.

  9. Interleukin-6 Prevents the Initiation but Enhances the Progression of Lung Cancer.

    PubMed

    Qu, Zhaoxia; Sun, Fan; Zhou, Jingjiao; Li, Liwen; Shapiro, Steven D; Xiao, Gutian

    2015-08-15

    Recent studies suggest that high expression of the proinflammatory cytokine IL6 is associated with poor survival of lung cancer patients. Accordingly, IL6 has been a target of great interest for lung cancer therapy. However, the role of IL6 in lung cancer has not been determined yet. Here, we demonstrate that IL6 plays opposite roles in the initiation and growth of lung cancer in a mouse model of lung cancer induced by the K-Ras oncogene. We find that compared with wild-type mice, IL6-deficient mice developed much more lung tumors after an activating mutant of K-Ras was induced in the lungs. However, lung tumors developed in IL6-deficient mice were significantly smaller. Notably, both the lung tumor-suppressing and -promoting functions of IL6 involve its ability in activating the transcription factor STAT3. IL6/STAT3 signaling suppressed lung cancer initiation through maintaining lung homeostasis, regulating lung macrophages, and activating cytotoxic CD8 T cells under K-Ras oncogenic stress, whereas it promoted lung cancer cell growth through inducing the cell proliferation regulator cyclin D1. These studies reveal a previously unexplored role of IL6/STAT3 signaling in maintaining lung homeostasis and suppressing lung cancer induction. These studies also significantly improve our understanding of lung cancer and provide a molecular basis for designing IL6/STAT3-targeted therapies for this deadliest human cancer.

  10. Epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of central nervous system metastases from non-small cell lung cancer: the present and the future

    PubMed Central

    Proto, Claudia; Imbimbo, Martina; Gallucci, Rosaria; Brissa, Angela; Signorelli, Diego; Vitali, Milena; Macerelli, Marianna; Corrao, Giulia; Ganzinelli, Monica; Greco, Francesca Gabriella; Garassino, Marina Chiara

    2016-01-01

    Lung cancer is one of the major causes of cancer related mortality worldwide. Brain metastases (BM) complicate clinical evolution of non-small cell lung cancer (NSCLC) in approximately 25–40% of cases, adversely influencing quality of life (QoL) and overall survival (OS). Systemic therapy remains the standard strategy for metastatic disease. Nevertheless, the blood-brain barrier (BBB) makes central nervous system (CNS) a sanctuary site. To date, the combination of chemotherapy with whole brain radiation therapy (WBRT), surgery and/or stereotactic radiosurgery (SRS) represents the most used treatment for patients (pts) with intracranial involvement. However, due to their clinical conditions, many pts are not able to undergo local treatments. Targeted therapies directed against epidermal growth factor receptor (EGFR), such as gefitinib, erlotinib and afatinib, achieved important improvements in EGFR mutated NSCLC with favorable toxicity profile. Although their role is not well defined, the reported objective response rate (ORR) and the good tolerance make EGFR-tyrosine kinase inhibitors (TKIs) an interesting valid alternative for NSCLC pts with BM, especially for those harboring EGFR mutations. Furthermore, new-generation TKIs, such as osimertinib and rociletinib, have already shown important activity on intracranial disease and several trials are still ongoing to evaluate their efficacy. In this review we want to highlight literature data about the use and the effectiveness of EGFR-TKIs in pts with BM from NSCLC. PMID:28149752

  11. Epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of central nervous system metastases from non-small cell lung cancer: the present and the future.

    PubMed

    Proto, Claudia; Imbimbo, Martina; Gallucci, Rosaria; Brissa, Angela; Signorelli, Diego; Vitali, Milena; Macerelli, Marianna; Corrao, Giulia; Ganzinelli, Monica; Greco, Francesca Gabriella; Garassino, Marina Chiara; Lo Russo, Giuseppe

    2016-12-01

    Lung cancer is one of the major causes of cancer related mortality worldwide. Brain metastases (BM) complicate clinical evolution of non-small cell lung cancer (NSCLC) in approximately 25-40% of cases, adversely influencing quality of life (QoL) and overall survival (OS). Systemic therapy remains the standard strategy for metastatic disease. Nevertheless, the blood-brain barrier (BBB) makes central nervous system (CNS) a sanctuary site. To date, the combination of chemotherapy with whole brain radiation therapy (WBRT), surgery and/or stereotactic radiosurgery (SRS) represents the most used treatment for patients (pts) with intracranial involvement. However, due to their clinical conditions, many pts are not able to undergo local treatments. Targeted therapies directed against epidermal growth factor receptor (EGFR), such as gefitinib, erlotinib and afatinib, achieved important improvements in EGFR mutated NSCLC with favorable toxicity profile. Although their role is not well defined, the reported objective response rate (ORR) and the good tolerance make EGFR-tyrosine kinase inhibitors (TKIs) an interesting valid alternative for NSCLC pts with BM, especially for those harboring EGFR mutations. Furthermore, new-generation TKIs, such as osimertinib and rociletinib, have already shown important activity on intracranial disease and several trials are still ongoing to evaluate their efficacy. In this review we want to highlight literature data about the use and the effectiveness of EGFR-TKIs in pts with BM from NSCLC.

  12. EGFR targeted therapy in lung cancer; an evolving story.

    PubMed

    Bartholomew, C; Eastlake, L; Dunn, P; Yiannakis, D

    2017-01-01

    Specific oncogenes with driver mutations, such as the Epidermal Growth Factor Receptor (EGFR 1) gene can lead to non-small-cell lung cancer formation. Identification of these oncogenes, their driver mutations and downstream effects allow the targeting of these pathways by drugs. Such personalised therapy has become an important strategy in combating lung cancer and highlights the need to test for these mutations. Tyrosine Kinase Inhibitors (TKIs) against EGFR, such as Erlotinib, are able to halt these tumour promoting properties in non-small-cell lung cancers. Third generation EGFR TKIs, such as Osimertinib, are focussing on resulting acquired TKI resistance. Here we report the clinical course of a patient with metastatic non-small-cell lung cancer who has undergone EGFR targeted therapy and been further challenged by TKI acquired resistance. Her extended survival and maintained quality of life are a consequence of these modern, genotype-targeted, personalised metastatic non-small-cell lung cancer therapies.

  13. Usefulness of circulating free DNA for monitoring epidermal growth factor receptor mutations in advanced non-small cell lung cancer patients: a case report

    PubMed Central

    Gonzalez-Cao, Maria; Ramirez, Santiago Viteri; Ariza, Nuria Jordana; Balada, Ariadna; Garzón, Mónica; Teixidó, Cristina; Karachaliou, Niki; Morales-Espinosa, Daniela; Molina-Vila, Miguel Ángel; Rosell, Rafael

    2016-01-01

    Genomic analysis of circulating tumor DNA (ctDNA) released from cancer cells into the bloodstream has been proposed as a useful method to capture dynamic changes during the course of the disease. In particular, the ability to monitor epidermal growth factor receptor (EGFR) mutation status in cell-free circulating DNA (cfDNA) isolated from advanced non-small cell lung cancer (NSCLC) patients EGFR can help to the correct management of the disease and overcome the challenges associated with tumor heterogeneity and insufficient biopsied material to perform key molecular diagnosis. Here, we report a case of long term monitorization of EGFR mutation status in cfDNA from peripheral blood in an NSCLC patient in, with excellent correlation with clinical evolution. PMID:27826535

  14. miR-223 enhances the sensitivity of non-small cell lung cancer cells to erlotinib by targeting the insulin-like growth factor-1 receptor.

    PubMed

    Zhao, Feng-Yi; Han, Jing; Chen, Xie-Wan; Wang, Jiang; Wang, Xu-Dong; Sun, Jian-Guo; Chen, Zheng-Tang

    2016-07-01

    Lung cancer is the leading cause of cancer-related fatalities worldwide, and non-small cell lung cancer (NSCLC) is the main pathological type. MicroRNAs (miRNAs or miRs) are a class of small non-coding RNAs, which are involved in tumor initiation and progression. miR‑223 is a tumor suppressor miRNA that has been reported in various types of cancer, including lung cancer. In the present study, to characterize the biological behavior of miR‑223 in NSCLC, we established an miR‑223 overexpression model in erlotinib-resistant PC‑9 (PC‑9/ER) cells by infection with lentivirus to induce the overexpression of miR‑223. As a result, miR‑223 enhanced the sensitivity of the PC‑9/ER cells to erlotinib by inducing apoptosis in vitro. Additionally, in vivo experiments were performed using nude mice which were injected with the cancer cells [either the PC‑9 (not resistant), PC‑9/ER, or the PC‑9/ER cells infected with miR‑223)]. We found that the tumor volumes were reduced in the rats injected with the cells infected with miR‑223. To further explore the underlying mechanisms, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot analysis were used to identify the target molecules of miR‑223. miR‑223 was demonstrated to act as a local regulator of insulin-like growth factor-1 receptor (IGF-1R) in the acquired resistance to tyrosine kinase inhibitors (TKIs). Notably, the οverexpression of IGF-1R in NSCLC was downregulated by miR‑223, and the activation of Akt/S6, the downstream pathway, was also inhibited. The inhibition of IGF-1R by miR‑223 was attenuated by exogenous IGF-1 expression. Therefore, miR‑223 may regulate the acquired resistance of PC‑9/ER cells to erlotinib by targeting the IGF-1R/Akt/S6 signaling pathway. The overexpression of miR‑223 may partially reverse the acquired resistance to epidermal growth factor receptor-TKIs, thus, providing a potential therapeutic strategy for TKI

  15. 78 FR 33851 - Lung Cancer Patient-Focused Drug Development; Public Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-06-05

    ... cancer. Lung cancer is a disease caused by uncontrolled growth of abnormal cells in the tissues of the lung, usually in the cells lining air passages. Lung cancer cells can spread (metastasize) to almost... disease (including surgery, radiation therapy, conventional chemotherapy, and targeted therapies),...

  16. Lung cancer therapeutics that target signaling pathways: an update.

    PubMed

    Ray, M Roshni; Jablons, David; He, Biao

    2010-10-01

    Claiming more than 150,000 lives each year, lung cancer is the deadliest cancer in the USA. First-line treatments in lung cancer include surgical resection and chemotherapy, the latter of which offers only modest survival benefits at the expense of often severe and debilitating side effects. Recent advances in elucidating the molecular biology of lung carcinogenesis have elucidated novel drug targets, and treatments are rapidly evolving into specialized agents that hone in on specific aspects of the disease. Of particular interest is blocking tumor growth by targeting the physiological processes surrounding angiogenesis, pro-tumorigenic growth factor activation, anti-apoptotic cascades and other cancer-promoting signal transduction events. This article looks at several areas of interest to lung cancer therapeutics and considers the current state of affairs surrounding the development of these therapies.

  17. Lung cancer in elderly patients

    PubMed Central

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

    2016-01-01

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

  18. Molecular Epidemiology of Female Lung Cancer

    PubMed Central

    Yim, Seon-Hee; Chung, Yeun-Jun

    2011-01-01

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

  19. [6]-Shogaol inhibits growth and induces apoptosis of non-small cell lung cancer cells by directly regulating Akt1/2

    PubMed Central

    Kim, Myoung Ok; Lee, Mee-Hyun; Oi, Naomi; Kim, Sung-Hyun; Dong, Zigang

    2014-01-01

    Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortality worldwide. Despite progress in developing chemotherapeutics for the treatment of NSCLC, primary and secondary resistance limits therapeutic success. NSCLC cells exhibit multiple mutations in the epidermal growth factor receptor (EGFR), which cause aberrant activation of diverse cell signaling pathways. Therefore, suppression of the inappropriate amplification of EGFR downstream signaling cascades is considered to be a rational therapeutic and preventive strategy for the management of NSCLC. Our initial molecular target–oriented virtual screening revealed that the ginger components, including [6]-shogaol, [6]-paradol and [6]-gingerol, seem to be potential candidates for the prevention and treatment of NSCLC. Among the compounds, [6]-shogaol showed the greatest inhibitory effects on the NSCLC cell proliferation and anchorage-independent growth. [6]-Shogaol induced cell cycle arrest (G1 or G2/M) and apoptosis. Furthermore, [6]-shogaol inhibited Akt kinase activity, a downstream mediator of EGFR signaling, by binding with an allosteric site of Akt. In NCI-H1650 lung cancer cells, [6]-shogaol reduced the constitutive phosphorylation of signal transducer and activator of transcription-3 (STAT3) and decreased the expression of cyclin D1/3, which are target proteins in the Akt signaling pathway. The induction of apoptosis in NCI-H1650 cells by [6]-shogaol corresponded with the cleavage of caspase-3 and caspase-7. Moreover, intraperitoneal administration of [6]-shogaol inhibited the growth of NCI-H1650 cells as tumor xenografts in nude mice. [6]-Shogaol suppressed the expression of Ki-67, cyclin D1 and phosphorylated Akt and STAT3 and increased terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positivity in xenograft tumors. The current study clearly indicates that [6]-shogaol can be exploited for the prevention and/or treatment of NSCLC. PMID:24282290

  20. Metastatic cancer to the lung

    MedlinePlus

    ... ray Lung with squamous cell cancer - CT scan Respiratory system References Arenberg DA, Pickens A. Metastatic malignant tumors. In: Broaddus VC, Mason RJ, Ernst JD, et al, eds. Murray and Nadel's Textbook of Respiratory Medicine . 6th ed. Philadelphia, PA: Elsevier Saunders; 2016: ...

  1. The matricellular protein CCN1 suppresses lung cancer cell growth by inducing senescence via the p53/p21 pathway.

    PubMed

    Jim Leu, Shr-Jeng; Sung, Jung-Sung; Chen, Mei-Yu; Chen, Chih-Wei; Cheng, Jian-Yu; Wang, Tse-Yen; Wang, Jeng-Jung

    2013-09-01

    CCN1, a secreted matrix-associated molecule, is involved in multiple cellular processes. Previous studies have indicated that expression of CCN1 correlates inversely with the aggressiveness of non-small-cell lung carcinoma (NSCLC); however, the underlying mechanisms remain elusive. Using three NSCLC cell line systems, here we show that long-term treatment of cells with the recombinant CCN1 protein led to a permanent cell cycle arrest in G1 phase; cells remained viable as judged by apoptotic assays. CCN1-treated NSCLC cells acquired a phenotype characteristic of senescent cells, including an enlarged and flattened cell shape and expression of the senescence-associated β-galactosidase. Immunoblot analysis showed that addition of CCN1 increased the abundance of hypo-phosphorylated Rb, as well as accumulation of p53 and p21. Silencing the expression of p53 or p21 by lentivirus-mediated shRNA production in cells blocked the CCN1-induced senescence. Furthermore, a CCN1 mutant defective for binding integrin α6β1 and co-receptor heparan sulfate proteoglycans was incapable of senescence induction. Our finding that direct addition of CCN1 induces senescence in NSCLC cells provides a potential novel strategy for therapeutic intervention of lung cancers.

  2. Suppressive effects of a proton beam on tumor growth and lung metastasis through the inhibition of metastatic gene expression in 4T1 orthotopic breast cancer model.

    PubMed

    Kwon, Yun-Suk; Lee, Kyu-Shik; Chun, So-Young; Jang, Tae Jung; Nam, Kyung-Soo

    2016-07-01

    A proton beam is a next generation tool to treat intractable cancer. Although the therapeutic effects of a proton beam are well known, the effect on tumor metastasis is not fully described. Here, we investigated the effects of a proton beam on metastasis in highly invasive 4T1 murine breast cancer cells and their orthotopic breast cancer model. Cells were irradiated with 2, 4, 8 or 16 Gy proton beam, and changes in cell proliferation, survival, and migration were observed by MTT, colony forming and wound healing assays. 4T1 breast cancer cell-implanted BALB/c mice were established and the animals were randomly divided into 4 groups when tumor size reached 200 mm3. Breast tumors were selectively irradiated with 10, 20 or 30 Gy proton beam. Breast tumor sizes were measured twice a week, and breast tumor and lung tissues were pathologically observed. Metastasis-regulating gene expression was assessed with quantitative RT-PCR. A proton beam dose-dependently decreased cell proliferation, survival and migration in 4T1 murine breast cancer cells. Also, growth of breast tumors in the 4T1 orthotopic breast cancer model was significantly suppressed by proton beam irradiation without significant change of body weight. Furthermore, fewer tumor nodules metastasized from breast tumor into lung in mice irradiated with 30 Gy proton beam, but not with 10 and 20 Gy, than in control. We observed correspondingly lower expression levels of urokinase plasminogen activator (uPA), uPA receptor, cyclooxygenase (COX)-2, and vascular endothelial growth factor (VEGF), which are important factors in cancer metastasis, in breast tumor irradiated with 30 Gy proton beam. Proton beam irradiation did not affect expressions of matrix metalloproteinase (MMP)-9 and MMP-2. Taken together, the data suggest that, although proton beam therapy is an effective tool for breast cancer treatment, a suitable dose is necessary to prevent metastasis-linked relapse and poor prognosis.

  3. Tyrosine Kinase Inhibitors in Lung Cancer

    PubMed Central

    Thomas, Anish; Rajan, Arun; Giaccone, Giuseppe

    2012-01-01

    SYNOPSIS ‘Driver mutations’ are essential for carcinogenesis as well as tumor progression as they confer a selective growth advantage to cancer cells. Identification of driver mutations in growth related protein kinases, especially tyrosine kinases have led to clinical development of an array of tyrosine kinase inhibitors in various malignancies, including lung cancer. Inhibition of epidermal growth factor receptor and anaplastic lymphoma kinase tyrosine kinases have proven to be of meaningful clinical benefit, while inhibition of several other tyrosine kinases have been of limited clinical benefit, thus far. An improved understanding of tyrosine kinase biology has also led to faster drug development, identification of resistance mechanisms and ways to overcome resistance. In this review, we discuss the clinical data supporting the use and practical aspects of management of patients on epidermal growth factor receptor and anaplastic lymphoma kinase tyrosine kinase inhibitors. PMID:22520981

  4. Epidermal growth factor receptor T790M mutation-positive metastatic non-small-cell lung cancer: focus on osimertinib (AZD9291)

    PubMed Central

    Saad, Nibal; Poudel, Aarati; Basnet, Alina; Gajra, Ajeet

    2017-01-01

    Adenocarcinoma is the most common type of non-small-cell lung cancer (NSCLC). Adenocarcinoma with epidermal growth factor receptor (EGFR) mutations accounts for 8%–30% of all cases of NSCLC depending on the geography and ethnicity. EGFR-mutated NSCLC usually responds to first-line therapy with EGFR tyrosine kinase inhibitors (TKIs). However, there is eventual loss of efficacy to TKIs due to development of resistance. The most frequent cause for resistance is a second EGFR mutation in exon 20 (T790M), which is encountered in up to 62% of patients. Osimertinib is one of the third-generation EGFR TKIs with a high selective potency against T790M mutants. In Phase I trial of osimertinib in advanced lung cancer after progression on EGFR TKIs, the response rate and disease control rate were 61% and 95%, respectively. A subsequent Phase II (AURA2) trial demonstrated a disease control rate of 92%, a response rate of 71%, a median duration of response of 7.8 months, and a median progression-free survival of 8.6 months. Osimertinib was approved by the US Food & Drug Administration in November 2015 for patients whose tumors exhibited T790M mutation and for those with progressive disease on other EGFR TKIs. In this review, we address the role of EGFR TKIs in the management of EGFR mutation lung cancer and the mechanisms of resistance to TKIs with a focus on the role of osimertinib. Data from completed trials of osimertinib, ongoing trials, as well as novel diagnostic methods to detect EGFR T790M mutation are reviewed. PMID:28367058

  5. Green tea polyphenol EGCG suppresses lung cancer cell growth through upregulating miR-210 expression caused by stabilizing HIF-1α.

    PubMed

    Wang, Hong; Bian, Shengjie; Yang, Chung S

    2011-12-01

    (-)-Epigallocatechin-3-gallate (EGCG) has been reported to affect many cellular regulatory pathways. This study aims to determine whether EGCG could target microRNA (miRNA), one of the mechanisms for cells to achieve subtle change in multiple targets. We found that, in both human and mouse lung cancer cells in culture, EGCG specifically upregulated the expression of miR-210, a major miRNA regulated by HIF-1α. Furthermore, we found that overexpression of miR-210 led to reduced cell proliferation rate and anchorage-independent growth as well as reduced sensitivity to EGCG. On the mechanisms of miR-210 regulation by EGCG, we demonstrated that the regulation was mediated through the hypoxia-response element in miR-210 promoter. Consistently, the upregulation of miR-210 was found to be correlated with the stabilized HIF-1α in lung cancer cell lines after EGCG treatment. This EGCG-induced stabilization of HIF-1α was further shown by the stabilization of HA-tagged HIF-1α but not the P402A/P564A-mutated HIF-1α by EGCG, suggesting that EGCG targets the oxygen-dependent degradation (ODD) domain. Direct evidence was obtained by affinity binding assay showing that EGCG specifically binds HIF-1α with a K(d) = 3.47 μM. This result suggests that EGCG binding interferes with the hydroxylation of key Pro residues in the ODD domain, preventing HIF-1α from the Pro hydroxylation-dependent ubiquitination and subsequent proteosome-mediated degradation. In summary, our results demonstrated, for the first time, the elevation of miR-210 by EGCG in lung cancer cell lines and this is mediated by the stabilization of HIF-1α. This event contributes to the anticancer activity of EGCG.

  6. Lung cancer-a fractal viewpoint.

    PubMed

    Lennon, Frances E; Cianci, Gianguido C; Cipriani, Nicole A; Hensing, Thomas A; Zhang, Hannah J; Chen, Chin-Tu; Murgu, Septimiu D; Vokes, Everett E; Vannier, Michael W; Salgia, Ravi

    2015-11-01

    Fractals are mathematical constructs that show self-similarity over a range of scales and non-integer (fractal) dimensions. Owing to these properties, fractal geometry can be used to efficiently estimate the geometrical complexity, and the irregularity of shapes and patterns observed in lung tumour growth (over space or time), whereas the use of traditional Euclidean geometry in such calculations is more challenging. The application of fractal analysis in biomedical imaging and time series has shown considerable promise for measuring processes as varied as heart and respiratory rates, neuronal cell characterization, and vascular development. Despite the advantages of fractal mathematics and numerous studies demonstrating its applicability to lung cancer research, many researchers and clinicians remain unaware of its potential. Therefore, this Review aims to introduce the fundamental basis of fractals and to illustrate how analysis of fractal dimension (FD) and associated measurements, such as lacunarity (texture) can be performed. We describe the fractal nature of the lung and explain why this organ is particularly suited to fractal analysis. Studies that have used fractal analyses to quantify changes in nuclear and chromatin FD in primary and metastatic tumour cells, and clinical imaging studies that correlated changes in the FD of tumours on CT and/or PET images with tumour growth and treatment responses are reviewed. Moreover, the potential use of these techniques in the diagnosis and therapeutic management of lung cancer are discussed.

  7. Key roles for GRB2-associated-binding protein 1, phosphatidylinositol-3-kinase, cyclooxygenase 2, prostaglandin E2 and transforming growth factor alpha in linoleic acid-induced upregulation of lung and breast cancer cell growth

    PubMed Central

    Johnson, E.D.; Beck, K.L.; Pardini, R.S.

    2014-01-01

    SUMMARY The omega-6 polyunsaturated fatty acid linoleic acid (LA; C18:2 n-6) is prevalent in Western diets and has been shown to enhance tumorigenesis of several cancer models. However, the modes by which LA affects carcinogenesis have not been fully elucidated. In this study, a mechanism for LA-induced upregulation of cancer cell growth is defined. Cellular proliferation was enhanced with LA treatment in BT-474 human breast ductal carcinoma and A549 human lung adenocarcinoma cell lines. Enrichment of LA increased COX activity and led to increases in PGE2 production, followed by increases in MMP and TGF-α levels, which are all key elements involved in the enhancement of cancer cell growth. Further investigation revealed that LA supplementation in both BT-474 breast and A549 lung cancer cell lines greatly increased the association between the scaffolding protein Gab1 and EGFR, while at the same time dramatically decreasing Gab1 protein levels. These changes are concomitant with increases in activated Akt (pAkt), a downstream signaling component in the PI3K signaling pathway. Moreover, inhibitors of EGFR, PI3K and Gab1-specific siRNAs were capable of reversing LA-induced upregulation of pAkt, as well as observed increases in cell proliferation for these models. These data establish Gab1 as major target in LA-induced enhancement of tumorigenesis. PMID:24374147

  8. Targeting oncogenic KRAS in non-small cell lung cancer cells by phenformin inhibits growth and angiogenesis

    PubMed Central

    Wang, Zhi Dong; Wei, Sheng Quan; Wang, Qin Yi

    2015-01-01

    Tumors require a vascular supply to grow and can achieve this via the expression of pro-angiogenic growth factors. Many potential oncogenic mutations have been identified in tumor angiogenesis. Somatic mutations in the small GTPase KRAS are the most common activating lesions found in human cancer, and are generally associated with poor response to standard therapies. Biguanides, such as the diabetes therapeutics metformin and phenformin, have demonstrated anti-tumor activity both in vitro and in vivo. The extracellular regulated protein kinases (ERK) signaling is known to be a major cellular target of biguanides. Based on KRAS activates several down-stream effectors leading to the stimulation of the RAF/mitogen-activated protein kinase/extracellular signal-regulated kinase (RAF/MEK/ERK) and phosphatidylinositol-3-kinase (PI3K) pathways, we investigated the anti-tumor effects of biguanides on the proliferation of KRAS-mutated tumor cells in vitro and on KRAS-driven tumor growth in vivo. In cancer cells harboring oncogenic KRAS, phenformin switches off the ERK pathway and inhibit the expression of pro-angiogenic molecules. In tumor xenografts harboring the KRAS mutation, phenformin extensively modifies the tumor growth causing abrogation of angiogenesis. These results strongly suggest that significant therapeutic advantage may be achieved by phenformin anti-angiogenesis for the treatment of tumor. PMID:26807315

  9. Practical use of advanced mouse models for lung cancer.

    PubMed

    Safari, Roghaiyeh; Meuwissen, Ralph

    2015-01-01

    recombinase activity into pulmonary tissues, and we discuss here the different techniques underlying these applications. Concomitant with Cre/Flp recombinase-based models are the tetracycline (Tet)-inducible bitransgenic systems in which presence or absence of doxycycline can turn the expression of a specific oncogene on or off. The use of several Tet-inducible lung cancer models for NSCLC is presented here in which the reversal of oncogene expression led to complete tumor regression and provided us with important insight of how oncogene dependence influence lung cancer survival and growth. As alternative to Tet-inducible models, we discuss the application of reversible expressed, transgenic mutant estrogen receptor (ER) fusion proteins, which are regulated via systemic tamoxifen administration. Most of the various lung cancer models can be combined through the generation of transgenic compound mice so that the use of these somatic mouse models can be even more enhanced for the study of specific molecular pathways that facilitate growth and maintenance of lung cancer. Finally, this description of the practical application and methodology of mouse models for lung cancer should be helpful in assisting researchers to make the best choices and optimal use of (existing) somatic models that suits the specific experimental needs in their study of lung cancer.

  10. Pleural involvement in lung cancer

    PubMed Central

    Giannou, Anastasios D.; Stathopoulos, Georgios T.

    2015-01-01

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

  11. Lung cancer screening and management.

    PubMed

    Jones, G S; Baldwin, D R

    2015-12-01

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

  12. v-rasH induces non-small cell phenotype, with associated growth factors and receptors, in a small cell lung cancer cell line.

    PubMed Central

    Falco, J P; Baylin, S B; Lupu, R; Borges, M; Nelkin, B D; Jasti, R K; Davidson, N E; Mabry, M

    1990-01-01

    Small cell lung cancer (SCLC) tumor progression can involve partial or complete conversion to a more treatment-resistant non-small cell (NSCLC) phenotype. In a cell culture model of this phenomenon, we have previously demonstrated that insertion of the viral Harvey ras gene (v-Ha-ras) into SCLC cell lines with amplification and overexpression of the c-myc gene induced many NSCLC phenotypic features. We now report that the v-Ha-ras gene can also induce morphologic, biochemical, and growth characteristics consistent with the NSCLC phenotype in an N-myc amplified SCLC cell line, NCI-H249. We show that v-Ha-ras has novel effects on these cells, abrogating an SCLC-specific growth requirement for gastrin-releasing peptide, and inducing mRNA expression of three NSCLC-associated growth factors and receptors, platelet-derived growth factor B chain, transforming growth factor-alpha (TGF-alpha), and epidermal growth factor receptor (EGF-R). TGF-alpha secretion and EGF-R also appear, consistent with the induction of an autocrine loop previously shown to be growth stimulatory for NSCLC in culture. These data suggest that N-myc and v-Ha-ras represent functional classes of genes that may complement each other in bringing about the phenotypic alterations seen during SCLC tumor progression, and suggest that such alterations might include the appearance of growth factors and receptors of potential importance for the growth of the tumor and its surrounding stroma. Images PMID:2161428

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

    ClinicalTrials.gov

    2014-08-04

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

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

    ClinicalTrials.gov

    2017-01-17

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

  15. Lung carcinogenesis from chronic obstructive pulmonary disease: characteristics of lung cancer from COPD and contribution of signal transducers and lung stem cells in the inflammatory microenvironment.

    PubMed

    Sekine, Yasuo; Hata, Atsushi; Koh, Eitetsu; Hiroshima, Kenzo

    2014-07-01

    Chronic obstructive pulmonary disease (COPD) and lung cancer are closely related. The annual incidence of lung cancer arising from COPD has been reported to be 0.8-1.7 %. Treatment of lung cancer from COPD is very difficult due to low cardiopulmonary function, rapid tumor growth, and resistance to molecularly targeted therapies. Chronic inflammation caused by toxic gases can induce COPD and lung cancer. Carcinogenesis in the inflammatory microenvironment occurs during cycles of tissue injury and repair. Cellular damage can induce induction of necrotic cell death and loss of tissue integrity. Quiescent normal stem cells or differentiated progenitor cells are introduced to repair injured tissues. However, inflammatory mediators may promote the growth of bronchioalveolar stem cells, and activation of NF-κB and signal transducer and activator of transcription 3 (STAT3) play crucial roles in the development of lung cancer from COPD. Many of the protumorgenic effects of NF-κB and STAT3 activation in immune cells are mediated through paracrine signaling. NF-κB and STAT3 also contribute to epithelial-mesenchymal transition. To improve lung cancer treatment outcomes, lung cancer from COPD must be overcome. In this article, we review the characteristics of lung cancer from COPD and the mechanisms of carcinogenesis in the inflammatory microenvironment. We also propose the necessity of identifying the mechanisms underlying progression of COPD to lung cancer, and comment on the clinical implications with respect to lung cancer prevention, screening, and therapy.

  16. Lung cancer: Biology and treatment options.

    PubMed

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

    2015-12-01

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

  17. MicroRNA-134 regulates lung cancer cell H69 growth and apoptosis by targeting WWOX gene and suppressing the ERK1/2 signaling pathway

    SciTech Connect

    Chen, Tianjun; Gao, Fei; Feng, Sifang; Yang, Tian; Chen, Mingwei

    2015-08-28

    MicroRNAs have been shown to act as crucial modulators during carcinogenesis. Recent studies have implied that miR-134 expression associated with epithelial-to-mesenchymal transition phenotype and invasive potential of NSCLC cells. Our study investigated the pathogenic implications of miR-134 in small cell lung cancer (SCLC). Overexpression or inhibition MiR-134 expression by miR-134 mimics or miR-134 inhibitors (anti-miR-134) in SCLC cell lines was detected using qRT-PCR. Lactate dehydrogenase (LDH) assay, MTT assays and flow cytometry were performed in order to clarify the growth and apoptosis of SCLC cells which had been transfected with miR-134 mimics or anti-miR-134. WWOX expression in H69 cells was detected by qRT-PCR and western blot, respectively. The results showed that overexpression miR-134 was significantly promoting SCLC cells growth and inhibit its apoptosis. In addition, reduced miR-134 expression was significantly correlated with cell growth inhibition and apoptosis promotion. Furthermore, transfection of miR-134 mimics into the SCLC cells markedly down-regulated the level of WWOX, whereas, anti-miR-134 up-regulated WWOX expression. We also found that overexpression WWOX attenuate miR-134 induced H69 cells growth, and promote cell apoptosis. Moreover, miR-134 promoted cell proliferation and inhibit apoptosis via the activation of ERK1/2 pathway. These findings suggest that miR-134 may be an ideal diagnostic and prognostic marker, and may be attributed to the molecular therapy of SCLC. - Highlights: • MiR-134 play roles in small cell lung cancer cell growth and apoptosis. • MiR-134 negative regulated the level of WWOX in H69 cells. • WWOX overexpression attenuate miR-134 induced H69 cells growth. • MiR-134 promotes cell growth via the activation of ERK1/2 pathway.

  18. Targeting Tyrosine Kinase Inhibitor-Resistant Non-Small Cell Lung Cancer by Inducing Epidermal Growth Factor Receptor Degradation via Methionine 790 Oxidation

    PubMed Central

    Leung, Elaine Lai-Han; Fan, Xing-Xing; Wong, Maria Pik; Jiang, Zhi-Hong; Liu, Zhong-Qiu; Yao, Xiao-Jun; Lu, Lin-Lin; Zhou, Yan-Ling; Yau, Li-Fong; Tin, Vicky Pui-Chi

    2016-01-01

    Abstract Aims: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been developed to treat non-small cell lung cancer (NSCLC) patients with EGFR mutation, but TKI resistance is common. Almost half of the acquired resistance patients are due to additional T790M mutation on EGFR (EGFRT790M), thus overcoming TKI resistance is important. In this study, we aim to investigate the role of reactive oxygen species (ROS) in TKI resistance as well as the molecular and biological effects of EGFRT790M after redox manipulation. Results: The basal ROS levels in EGFRT790M-containing TKI-resistant NSCLC cell lines were substantially high. Sixty-three human lung tumors showed higher NADPH oxidase isoform 2 (NOX2) expression than normal lung tissues, which may contribute to high basal ROS in cancer and poor survival. Interestingly, only NOX3 was upregulated by sanguinarine, a pharmacological agent to elevate ROS, and resulted in EGFR overoxidation, degradation, and apoptosis. By contrast, such responses were lacking in EGFRWT cells. Selective EGFRT790M degradation was manipulated by redox imbalance between NOX3 and methionine reductase A (MsrA). Furthermore, the in vivo tumor suppression effect of sanguinarine, NOX3 upregulation, and EGFR degradation were confirmed. Innovation: We have found a new treatment strategy to overcome TKI resistance by selectively inducing EGFRT790M degradation via specific stimulation of methionine 790 (M790) oxidation. It can be achieved via manipulating redox imbalance between NOX3 and MsrA. Conclusion: Targeting EGFR by elevating ROS and redox imbalance is a potential new strategy to develop a new EGFR inhibitor for TKI-resistant patients with a wide therapeutic window between EGFRT790M and EGFRWT. Antioxid. Redox Signal. 24, 263–279. PMID:26528827

  19. Lung cancer stem cells—characteristics, phenotype

    PubMed Central

    George, Rachel; Sethi, Tariq

    2016-01-01

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

  20. Multifaceted roles of cyclooxygenase-2 in lung cancer.

    PubMed

    Riedl, Karen; Krysan, Kostyantyn; Põld, Mehis; Dalwadi, Harnisha; Heuze-Vourc'h, Nathalie; Dohadwala, Mariam; Liu, Ming; Cui, Xiaoyan; Figlin, Robert; Mao, Jenny T; Strieter, Robert; Sharma, Sherven; Dubinett, Steven M

    2004-06-01

    Lung cancer is the leading cause of cancer death in the United States. Although the low 5-year survival rate (under 15%) has changed minimally in the last 25 years, new agents and combinations of agents that target tumor proliferation, invasion, and survival may lead to improvement in patient outcomes. There is evidence that cyclooxygenase-2 (COX-2) is overexpressed in lung cancer and promotes tumor proliferation, invasion, angiogenesis, and resistance to apoptosis. COX-2 inhibitors have been found to inhibit tumor growth in animal models and have demonstrated responses when combined with conventional therapy in phase II clinical trials. Further understanding of the mechanisms involved in COX-2-mediated tumorigenesis and its interaction with other molecules in lung cancer may lead to improved therapeutic strategies for this disease. In addition, delineation of how COX-2-dependent genes modulate the malignant phenotype will provide novel insights in lung cancer pathogenesis.

  1. [Cannabis smoking and lung cancer].

    PubMed

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

    2014-06-01

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

  2. KLF4 regulates adult lung tumor-initiating cells and represses K-Ras-mediated lung cancer.

    PubMed

    Yu, T; Chen, X; Zhang, W; Liu, J; Avdiushko, R; Napier, D L; Liu, A X; Neltner, J M; Wang, C; Cohen, D; Liu, C

    2016-02-01

    Lung cancer is the leading cause of cancer-related mortality in both men and women worldwide. To identify novel factors that contribute to lung cancer pathogenesis, we analyzed a lung cancer database from The Cancer Genome Atlas and found that Krüppel-like Factor 4 (KLF4) expression is significantly lower in patients' lung cancer tissue than in normal lung tissue. In addition, we identified seven missense mutations in the KLF4 gene. KLF4 is a transcription factor that regulates cell proliferation and differentiation as well as the self-renewal of stem cells. To understand the role of KLF4 in the lung, we generated a tamoxifen-induced Klf4 knockout mouse model. We found that KLF4 inhibits lung cancer cell growth and that depletion of Klf4 altered the differentiation pattern in the developing lung. To understand how KLF4 functions during lung tumorigenesis, we generated the K-ras(LSL-G12D/+);Klf4(fl/fl) mouse model, and we used adenovirus-expressed Cre to induce K-ras activation and Klf4 depletion in the lung. Although Klf4 deletion alone or K-ras mutation alone can trigger lung tumor formation, Klf4 deletion combined with K-ras mutation significantly enhanced lung tumor formation. We also found that Klf4 deletion in conjunction with K-ras activation caused lung inflammation. To understand the mechanism whereby KLF4 is regulated during lung tumorigenesis, we analyzed KLF4 promoter methylation and the profiles of epigenetic factors. We found that Class I histone deacetylases (HDACs) are overexpressed in lung cancer and that HDAC inhibitors induced expression of KLF4 and inhibited proliferation of lung cancer cells, suggesting that KLF4 is probably repressed by histone acetylation and that HDACs are valuable drug targets for lung cancer treatment.

  3. Lung Cancer Awareness Week

    ERIC Educational Resources Information Center

    Glennon, Catherine; Laczko, Lori

    2003-01-01

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

  4. LUCIS: lung cancer imaging studies.

    PubMed

    Harders, Stefan Walbom

    2012-11-01

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

  5. Fyn mediates transforming growth factor-beta1-induced down-regulation of E-cadherin in human A549 lung cancer cells.

    PubMed

    Kim, An Na; Jeon, Woo-Kwang; Lim, Kyu-Hyoung; Lee, Hui-Young; Kim, Woo Jin; Kim, Byung-Chul

    2011-04-01

    Transforming growth factor-beta (TGF-β) signaling positively contributes to the regulation of tumor metastasis. However, the underlying molecular mechanisms are less well defined. We here show that Fyn, a member of Src family tyrosine kinases, plays a critical role in mediating TGF-β1-induced down-regulation of E-cadherin in human A549 lung cancer cells. Blockade of Fyn with siRNA knockdown or ligand-binding defective mutant significantly lowered the ability of TGF-β1 to repress E-cadherin expression. Furthermore, our results demonstrated that Fyn facilitates TGF-β1-mediated suppression of E-cadherin through p38 kinase-dependent induction of Snail. Collectively, our findings identify a Fyn-p38-Snail cascade as a new signaling pathway mediating oncogenic TGF-β function.

  6. Mer or Axl receptor tyrosine kinase inhibition promotes apoptosis, blocks growth and enhances chemosensitivity of human non-small cell lung cancer.

    PubMed

    Linger, R M A; Cohen, R A; Cummings, C T; Sather, S; Migdall-Wilson, J; Middleton, D H G; Lu, X; Barón, A E; Franklin, W A; Merrick, D T; Jedlicka, P; DeRyckere, D; Heasley, L E; Graham, D K

    2013-07-18

    Non-small cell lung cancer (NSCLC) is a prevalent and devastating disease that claims more lives than breast, prostate, colon and pancreatic cancers combined. Current research suggests that standard chemotherapy regimens have been optimized to maximal efficiency. Promising new treatment strategies involve novel agents targeting molecular aberrations present in subsets of NSCLC. We evaluated 88 human NSCLC tumors of diverse histology and identified Mer and Axl as receptor tyrosine kinases (RTKs) overexpressed in 69% and 93%, respectively, of tumors relative to surrounding normal lung tissue. Mer and Axl were also frequently overexpressed and activated in NSCLC cell lines. Ligand-dependent Mer or Axl activation stimulated MAPK, AKT and FAK signaling pathways indicating roles for these RTKs in multiple oncogenic processes. In addition, we identified a novel pro-survival pathway-involving AKT, CREB, Bcl-xL, survivin, and Bcl-2-downstream of Mer, which is differentially modulated by Axl signaling. We demonstrated that short hairpin RNA (shRNA) knockdown of Mer or Axl significantly reduced NSCLC colony formation and growth of subcutaneous xenografts in nude mice. Mer or Axl knockdown also improved in vitro NSCLC sensitivity to chemotherapeutic agents by promoting apoptosis. When comparing the effects of Mer and Axl knockdown, Mer inhibition exhibited more complete blockade of tumor growth while Axl knockdown more robustly improved chemosensitivity. These results indicate that Mer and Axl have complementary and overlapping roles in NSCLC and suggest that treatment strategies targeting both RTKs may be more effective than singly-targeted agents. Our findings validate Mer and Axl as potential therapeutic targets in NSCLC and provide justification for development of novel therapeutic compounds that selectively inhibit Mer and/or Axl.

  7. Chinese Herbal Medicine Fuzheng Kang-Ai Decoction Inhibited Lung Cancer Cell Growth through AMPKα-Mediated Induction and Interplay of IGFBP1 and FOXO3a

    PubMed Central

    Zheng, Fang; Wu, Jingjing; Li, Xiong; Tang, Qing; Yang, LiJun; Yang, Xiaobing; Wu, WanYin

    2016-01-01

    The aim of this study is to investigate the actions of Chinese herbal medicine, called “Fuzheng Kang-Ai” (FZKA for short) decoction, against non-small cell lung cancer (NSCLC) and its mechanisms in vitro and in vivo. We showed that the effect of FZKA decoction significantly inhibited growth of A549 and PC9 cells. Furthermore, FZKA increased phosphorylation of AMP-activated protein kinase alpha (AMPKα) and induced protein expression of insulin-like growth factor (IGF) binding protein 1 (IGFBP1) and forkhead homeobox type O3a (FOXO3a). The specific inhibitor of AMPKα (Compound C) blocked FZKA-induced protein expression of IGFBP1 and FOXO3a. Interestingly, silencing of IGFBP1 and FOXO3a overcame the inhibitory effect of FZKA on cell growth. Moreover, silencing of IGFBP1 attenuated the effect of FZKA decoction on FOXO3a expression, and exogenous expression of FOXO3a enhanced the FZKA-stimulated phosphorylation of AMPKα. Accordingly, FZKA inhibited the tumor growth in xenograft nude mice model. Collectively, our results show that FZKA decoction inhibits proliferation of NSCLC cells through activation of AMPKα, followed by induction of IGFBP1 and FOXO3a proteins. Exogenous expression of FOXO3a feedback enhances FZKA decoction-stimulated IGFBP1 expression and phosphorylation of AMPKα. The reciprocal interplay of IGFBP1 and FOXO3a contribute to the overall responses of FAKA decoction. PMID:27057199

  8. Hyperspectral imaging of skin and lung cancers

    NASA Astrophysics Data System (ADS)

    Zherdeva, Larisa A.; Bratchenko, Ivan A.; Alonova, Marina V.; Myakinin, Oleg O.; Artemyev, Dmitry N.; Moryatov, Alexander A.; Kozlov, Sergey V.; Zakharov, Valery P.

    2016-04-01

    The problem of cancer control requires design of new approaches for instrumental diagnostics, as the accuracy of cancer detection on the first step of diagnostics in clinics is slightly more than 50%. In this study, we present a method of visualization and diagnostics of skin and lung tumours based on registration and processing of tissues hyperspectral images. In a series of experiments registration of hyperspectral images of skin and lung tissue samples is carried out. Melanoma, basal cell carcinoma, nevi and benign tumours are studied in skin ex vivo and in vivo experiments; adenocarcinomas and squamous cell carcinomas are studied in ex vivo lung experiments. In a series of experiments the typical features of diffuse reflection spectra for pathological and normal tissues were found. Changes in tissues morphology during the tumour growth lead to the changes of blood and pigments concentration, such as melanin in skin. That is why tumours and normal tissues maybe differentiated with information about spectral response in 500-600 nm and 600 - 670 nm areas. Thus, hyperspectral imaging in the visible region may be a useful tool for cancer detection as it helps to estimate spectral properties of tissues and determine malignant regions for precise resection of tumours.

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

    Cancer.gov

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

  10. The β-TrCP-FBXW2-SKP2 axis regulates lung cancer cell growth with FBXW2 acting as a tumour suppressor

    PubMed Central

    Xu, Jie; Zhou, Weihua; Yang, Fei; Chen, Guoan; Li, Haomin; Zhao, Yongchao; Liu, Pengyuan; Li, Hua; Tan, Mingjia; Xiong, Xiufang; Sun, Yi

    2017-01-01

    β-TrCP and SKP2 are two well-studied F-box proteins, which often act as oncogenes. Whether and how they communicate with each other is unknown. Here we report that FBXW2, a poorly characterized F-box, is a substrate of β-TrCP1 and an E3 ligase for SKP2. While β-TrCP1 promotes FBXW2 ubiquitylation and shortens its half-life, FBXW2 does the same to SKP2. FBXW2 has tumour suppressor activity against lung cancer cells and blocks oncogenic function of both β-TrCP1 and SKP2. The levels of β-TrCP1-FBXW2-SKP2 are inversely correlated during cell cycle with FBXW2 and β-TrCP/SKP2 being high or low, respectively, in arrested cells, whereas the opposite is true in proliferating cells. Consistently, FBXW2 predicts a better patient survival, whereas β-TrCP1 and SKP2 predict a worse survival. Finally, the gain- and loss-of-function mutations of FBXW2 are found in various human cancers. Collectively, our data show that the β-TrCP-FBXW2-SKP2 axis forms an oncogene-tumour suppressor-oncogene cascade to control cancer cell growth with FBXW2 acting as a tumour suppressor by promoting SKP2 degradation. PMID:28090088

  11. Blockade of Hedgehog Signaling Synergistically Increases Sensitivity to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Non-Small-Cell Lung Cancer Cell Lines

    PubMed Central

    Bai, Xiao-Yan; Zhang, Xu-Chao; Yang, Su-Qing; An, She-Juan; Chen, Zhi-Hong; Su, Jian; Xie, Zhi; Gou, Lan-Ying; Wu, Yi-Long

    2016-01-01

    Aberrant activation of the hedgehog (Hh) signaling pathway has been implicated in the epithelial-to-mesenchymal transition (EMT) and cancer stem-like cell (CSC) maintenance; both processes can result in tumor progression and treatment resistance in several types of human cancer. Hh cooperates with the epidermal growth factor receptor (EGFR) signaling pathway in embryogenesis. We found that the Hh signaling pathway was silenced in EGFR-TKI-sensitive non-small-cell lung cancer (NSCLC) cells, while it was inappropriately activated in EGFR-TKI-resistant NSCLC cells, accompanied by EMT induction and ABCG2 overexpression. Upregulation of Hh signaling through extrinsic SHH exposure downregulated E-cadherin expression and elevated Snail and ABCG2 expression, resulting in gefitinib tolerance (P < 0.001) in EGFR-TKI-sensitive cells. Blockade of the Hh signaling pathway using the SMO antagonist SANT-1 restored E-cadherin expression and downregulate Snail and ABCG2 in EGFR-TKI-resistant cells. A combination of SANT-1 and gefitinib markedly inhibited tumorigenesis and proliferation in EGFR-TKI-resistant cells (P < 0.001). These findings indicate that hyperactivity of Hh signaling resulted in EGFR-TKI resistance, by EMT introduction and ABCG2 upregulation, and blockade of Hh signaling synergistically increased sensitivity to EGFR-TKIs in primary and secondary resistant NSCLC cells. E-cadherin expression may be a potential biomarker of the suitability of the combined application of an Hh inhibitor and EGFR-TKIs in EGFR-TKI-resistant NSCLCs. PMID:26943330

  12. FOXP4 modulates tumor growth and independently associates with miR-138 in non-small cell lung cancer cells.

    PubMed

    Yang, Tian; Li, Hong; Thakur, Asmitananda; Chen, Tianjun; Xue, Jing; Li, Dan; Chen, Mingwei

    2015-09-01

    Family of forkhead box transcription factors, including forkhead box P4 (FOXP4), plays an important role in oncogenesis. The current study is to evaluate the role of FOXP4 in regulating human non-small cell lung cancer (NSCLC). Quantitative RT-PCR and Western blot were performed to evaluate the gene and protein expressions of FOXP4 in six NSCLC cell lines and 55 NSCLC patients. Lentivirus of small hairpin RNA (FOXP4-shRNA) was used to downregulate FOXP4 in NSCLC cell lines A549 and H1703 cells. Its effect on NSCLC growth, invasion, and cell cycle were evaluated by cell proliferation assay, migration assay, and cell cycle assay, respectively. Dual luciferase assay and Western blot were used to examine whether microRNA-138 (miR-138) was an upstream regulator of FOXP4. The dependence of FOXP4 on miR-138 associated signaling pathway was evaluated by ectopically overexpressing enhancer of zeste homolog 2 (EZH2), a known miR-138 target in NSCLC. FOXP4 was highly expressed in both NSCLC cell lines and NSCLC patients. FOXP4 downregulation by FOXP4-shRNA markedly reduced cancer cell growth and invasion, as well as induced cell cycle arrest in A549 and H1703 cells. MiR-138 was confirmed to be an upstream regulator of FOXP4 and directly regulated FOXP4 expression in A549 and H1703 cells. FOXP4 downregulation-mediated inhibition on cancer cell growth and invasion was independent on overexpressing EZH2, another direct target of miR-138 in NSCLC. Our data demonstrated that FOXP4 was a critical regulator in NSCLC and independently associated with miR-138 regulation.

  13. The Current and Evolving Role of PET in Personalized Management of Lung Cancer.

    PubMed

    Mena, Esther; Yanamadala, Anusha; Cheng, Gang; Subramaniam, Rathan M

    2016-07-01

    Using tumor genomic profiling information has revolutionized the landscape of personalized treatment of lung cancer. The management of lung cancer and non-small cell lung cancer particularly is influenced by discoveries of activating mutations in epidermal growth factor receptor and targeted therapies with tyrosine kinase inhibitors, fusion genes involving anaplastic lymphoma kinase, and targeted therapies for Kristen-Rat-Sarcoma and MET protooncogenes. PET imaging plays an important role in assessing the biologic behavior of lung cancer and defining response to therapy. This review summarizes genomic discoveries in lung cancer and their implications for functional PET imaging.

  14. Downregulation of miR-497 promotes tumor growth and angiogenesis by targeting HDGF in non-small cell lung cancer

    SciTech Connect

    Zhao, Wen-yan; Wang, Yan; An, Zhong-jun; Shi, Chang-guo; Zhu, Guang-ai; Wang, Bin; Lu, Ming-yan; Pan, Chang-kun; Chen, Peng

    2013-06-07

    Highlights: •MiR-497 is down-regulated in NSCLC cells and tissues. •MiR-497 inhibits NSCLC cell growth in vitro. •HDGF is a target gene of miR-497. •MiR-497 inhibits NSCLC cell growth by downregulating HDGF. •miR-497 inhibits tumor growth and angiogenesis in vivo. -- Abstract: MicroRNAs (miRNAs) play important roles in the development of various cancers. MiRNA-497 functions as a tumor-suppressor that is downregulated in several malignancies; however, its role in non-small cell lung cancer (NSCLC) has not been examined in detail. Here, we showed that miR-497 is downregulated in NSCLC tumors and cell lines and its ectopic expression significantly inhibits cell proliferation and colony formation. Integrated analysis identified HDGF as a downstream target of miR-497, and the downregulation of HDGF by miR-497 overexpression confirmed their association. Rescue experiments showed that the inhibitory effect of miR-497 on cell proliferation and colony formation is predominantly mediated by the modulation of HDGF levels. Furthermore, tumor samples from NSCLC patients showed an inverse relationship between miR-497 and HDGF levels, and ectopic expression of miR-497 significantly inhibited tumor growth and angiogenesis in a SCID mouse xenograft model. Our results suggest that miR-497 may serve as a biomarker in NSCLC, and the modulation of its activity may represent a novel therapeutic strategy for the treatment of NSCLC patients.

  15. Combined treatment of XIAP-targeting shRNA and celecoxib synergistically inhibits the tumor growth of non‑small cell lung cancer cells in vitro and in vivo.

    PubMed

    Zhang, Hong; Li, Zhihong; Wang, Kaizhong; Ren, Ping

    2015-03-01

    X-linked inhibitor of apoptosis protein (XIAP) has been shown to be highly expressed in lung cancer, but not in normal lung tissue, which makes it an attractive target for lung cancer treatment. Celecoxib (CXB), a cyclooxygenase-2 inhibitor, is in wide clinical use for the treatment and prevention of non-small cell lung cancer (NSCLC). Therefore, in our study, we combined short hairpin RNA (shRNA) targeted to XIAP (XIAP-shRNA) with CXB and tested the effects of this combination on lung cancer cells to identify more effective therapeutics against lung cancer. An XIAP-shRNA plasmid was constructed and transfected into the A549 NSCLC cell line. The cells were then treated with CXB and XIAP-shRNA alone or in combination for indicated time periods, and the treatments were assessed for their effects on cell proliferation, apoptosis, migration, invasion and receptor signaling using the MTT, TUNEL, wound healing and Matrigel invasion assays and western blotting, respectively. In addition, an NSCLC xenograft model was prepared to observe tumor growth. It was found that both CXB and XIAP‑shRNA significantly inhibited cell proliferation, migration and invasion, and induced cell apoptosis in vitro, as well as suppressed tumor growth in vivo. Moreover, the combination of the agents significantly enhanced these effects compared to the single agent treatments. We also found that the combination treatment significantly suppressed constitutive phosphorylation of PI3K and AKT, which may contribute to the inhibition of tumor growth. These findings suggest that the combination of XIAP‑shRNA and CXB is a promising drug candidate for the treatment of NSCLC.

  16. [Lung cancer and lymph drainage].

    PubMed

    Riquet, M

    2007-01-01

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

  17. Functions and mechanisms of long noncoding RNAs in lung cancer

    PubMed Central

    Peng, Zhenzi; Zhang, Chunfang; Duan, Chaojun

    2016-01-01

    Lung cancer is a heterogeneous disease, and there is a lack of adequate biomarkers for diagnosis. Long noncoding RNAs (lncRNAs) are emerging as an important set of molecules because of their roles in various key pathophysiological pathways, including cell growth, apoptosis, and metastasis. We review the current knowledge of the lncRNAs in lung cancer. In-depth analyses of lncRNAs in lung cancer have increased the number of potential effective biomarkers, thus providing options to increase the therapeutic benefit. In this review, we summarize the functions, mechanisms, and regulatory networks of lncRNAs in lung cancer, providing a basis for further research in this field. PMID:27499635

  18. Diet-derived 25-hydroxyvitamin D3 activates vitamin D receptor target gene expression and suppresses EGFR mutant non-small cell lung cancer growth in vitro and in vivo

    PubMed Central

    Verone-Boyle, Alissa R.; Shoemaker, Suzanne; Attwood, Kristopher; Morrison, Carl D.; Makowski, Andrew J.; Battaglia, Sebastiano; Hershberger, Pamela A.

    2016-01-01

    Epidemiologic studies implicate vitamin D status as a factor that influences growth of EGFR mutant lung cancers. However, laboratory based evidence of the biological effect of vitamin D in this disease is lacking. To fill this knowledge gap, we determined vitamin D receptor (VDR) expression in human lung tumors using a tissue microarray constructed of lung cancer cases from never-smokers (where EGFR gene mutations are prevalent). Nuclear VDR was detected in 19/19 EGFR mutant tumors. Expression tended to be higher in tumors with EGFR exon 19 deletions than those with EGFR L858R mutations. To study anti-proliferative activity and signaling, EGFR mutant lung cancer cells were treated with the circulating metabolite of vitamin D, 25-hydroxyvitamin D3 (25D3). 25D3 inhibited clonogenic growth in a dose-dependent manner. CYP27B1 encodes the 1α-hydroxylase (1αOHase) that converts 25D3 to the active metabolite, 1,25-dihydroxyvitamin D3 (1,25D3). Studies employing VDR siRNA, CYP27B1 zinc finger nucleases, and pharmacologic inhibitors of the vitamin D pathway indicate that 25D3 regulates gene expression in a VDR-dependent manner but does not strictly require 1αOHase-mediated conversion of 25D3 to 1,25D3. To determine the effects of modulating serum 25D3 levels on growth of EGFR mutant lung tumor xenografts, mice were fed diets containing 100 or 10,000 IU vitamin D3/kg. High dietary vitamin D3 intake resulted in elevated serum 25D3 and significant inhibition of tumor growth. No toxic effects of supplementation were observed. These results identify EGFR mutant lung cancer as a vitamin D-responsive disease and diet-derived 25D3 as a direct VDR agonist and therapeutic agent. PMID:26654942

  19. Imaging Primary Lung Cancers in Mice to Study Radiation Biology

    SciTech Connect

    Kirsch, David G.; Grimm, Jan; Guimaraes, Alexander R.; Wojtkiewicz, Gregory R.; Perez, Bradford A.; Santiago, Philip M.; Anthony, Nikolas K.; Forbes, Thomas; Doppke, Karen

    2010-03-15

    Purpose: To image a genetically engineered mouse model of non-small-cell lung cancer with micro-computed tomography (micro-CT) to measure tumor response to radiation therapy. Methods and Materials: The Cre-loxP system was used to generate primary lung cancers in mice with mutation in K-ras alone or in combination with p53 mutation. Mice were serially imaged by micro-CT, and tumor volumes were determined. A comparison of tumor volume by micro-CT and tumor histology was performed. Tumor response to radiation therapy (15.5 Gy) was assessed with micro-CT. Results: The tumor volume measured with free-breathing micro-CT scans was greater than the volume calculated by histology. Nevertheless, this imaging approach demonstrated that lung cancers with mutant p53 grew more rapidly than lung tumors with wild-type p53 and also showed that radiation therapy increased the doubling time of p53 mutant lung cancers fivefold. Conclusions: Micro-CT is an effective tool to noninvasively measure the growth of primary lung cancers in genetically engineered mice and assess tumor response to radiation therapy. This imaging approach will be useful to study the radiation biology of lung cancer.

  20. Study of the Effects of Betaine and/or C-Phycocyanin on the Growth of Lung Cancer A549 Cells In Vitro and In Vivo.

    PubMed

    Bingula, Rea; Dupuis, Carmen; Pichon, Chantal; Berthon, Jean-Yves; Filaire, Marc; Pigeon, Lucie; Filaire, Edith

    2016-01-01

    We investigated the effects of betaine, C-phycocyanin (C-PC), and their combined use on the growth of A549 lung cancer both in vitro and in vivo. When cells were coincubated with betaine and C-PC, an up to 60% decrease in viability was observed which is significant compared to betaine (50%) or C-PC treatment alone (no decrease). Combined treatment reduced the stimulation of NF-κB expression by TNF-α and increased the amount of the proapoptotic p38 MAPK. Interestingly, combined treatment induced a cell cycle arrest in G2/M phase for ~60% of cells. In vivo studies were performed in pathogen-free male nude rats injected with A549 cells in their right flank. Their daily food was supplemented with either betaine, C-PC, both, or neither. Compared to the control group, tumour weights and volumes were significantly reduced in either betaine- or C-PC-treated groups and no additional decrease was obtained with the combined treatment. This data indicates that C-PC and betaine alone may efficiently inhibit tumour growth in rats. The synergistic activity of betaine and C-PC on A549 cells growth observed in vitro remains to be further confirmed in vivo. The reason behind the nature of their interaction is yet to be sought.

  1. Study of the Effects of Betaine and/or C-Phycocyanin on the Growth of Lung Cancer A549 Cells In Vitro and In Vivo

    PubMed Central

    Pichon, Chantal; Pigeon, Lucie

    2016-01-01

    We investigated the effects of betaine, C-phycocyanin (C-PC), and their combined use on the growth of A549 lung cancer both in vitro and in vivo. When cells were coincubated with betaine and C-PC, an up to 60% decrease in viability was observed which is significant compared to betaine (50%) or C-PC treatment alone (no decrease). Combined treatment reduced the stimulation of NF-κB expression by TNF-α and increased the amount of the proapoptotic p38 MAPK. Interestingly, combined treatment induced a cell cycle arrest in G2/M phase for ~60% of cells. In vivo studies were performed in pathogen-free male nude rats injected with A549 cells in their right flank. Their daily food was supplemented with either betaine, C-PC, both, or neither. Compared to the control group, tumour weights and volumes were significantly reduced in either betaine- or C-PC-treated groups and no additional decrease was obtained with the combined treatment. This data indicates that C-PC and betaine alone may efficiently inhibit tumour growth in rats. The synergistic activity of betaine and C-PC on A549 cells growth observed in vitro remains to be further confirmed in vivo. The reason behind the nature of their interaction is yet to be sought. PMID:27635139

  2. Antioxidants accelerate lung cancer progression in mice.

    PubMed

    Sayin, Volkan I; Ibrahim, Mohamed X; Larsson, Erik; Nilsson, Jonas A; Lindahl, Per; Bergo, Martin O

    2014-01-29

    Antioxidants are widely used to protect cells from damage induced by reactive oxygen species (ROS). The concept that antioxidants can help fight cancer is deeply rooted in the general population, promoted by the food supplement industry, and supported by some scientific studies. However, clinical trials have reported inconsistent results. We show that supplementing the diet with the antioxidants N-acetylcysteine (NAC) and vitamin E markedly increases tumor progression and reduces survival in mouse models of B-RAF- and K-RAS-induced lung cancer. RNA sequencing revealed that NAC and vitamin E, which are structurally unrelated, produce highly coordinated changes in tumor transcriptome profiles, dominated by reduced expression of endogenous antioxidant genes. NAC and vitamin E increase tumor cell proliferation by reducing ROS, DNA damage, and p53 expression in mouse and human lung tumor cells. Inactivation of p53 increases tumor growth to a similar degree as antioxidants and abolishes the antioxidant effect. Thus, antioxidants accelerate tumor growth by disrupting the ROS-p53 axis. Because somatic mutations in p53 occur late in tumor progression, antioxidants may accelerate the growth of early tumors or precancerous lesions in high-risk populations such as smokers and patients with chronic obstructive pulmonary disease who receive NAC to relieve mucus production.

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

    ClinicalTrials.gov

    2017-02-20

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

  4. Screening and early detection of lung cancer.

    PubMed

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

    2011-01-01

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

  5. MicroRNA-92a promotes growth, metastasis, and chemoresistance in non-small cell lung cancer cells by targeting PTEN.

    PubMed

    Ren, Ping; Gong, Fangchao; Zhang, Yan; Jiang, Jindong; Zhang, Hong

    2016-03-01

    MicroRNA-92a (miR-92a) has been reported to play important roles in tumorigenesis of human various cancers. However, the roles and underlying molecular mechanism of miR-92a in non-small cell lung cancer (NSCLC) have not been totally elucidated. Therefore, the aims of this study were to determine the role of miR-92a and to elucidate its regulatory mechanism in NSCLC. We found that miR-92a was significantly upregulated in NSCLC tissues compared to matched adjacent normal lung tissues, and its expression is significantly associated with clinical characteristics of patients, including tumor, node, and metastasis (TNM) stage; tumor size; and lymph node metastasis (all P < 0.01). Function assays demonstrated that upregulation of miR-92a in NSCLC cells promoted cell proliferation, migration, and invasion, decreased apoptosis and caspase-3 activity, and enhanced chemoresistance of NSCLC cells, whereas downregulation of miR-92a showed the opposite effects. Moreover, phosphatase and tensin homolog (PTEN), a unique tumor suppressor gene, was confirmed as a direct target of miR-92a, and PTEN messenger RNA (mRNA) expression was decreased in NSCLC tissues and was inversely correlated with miR-92a. Downregulation of PTEN could mimic the same effects of miR-92a mimic in NSCLC cells and rescue the effects on NSCLC cells induced by miR-92a inhibitor. Taken together, these findings suggested that miR-92a could promote growth, metastasis, and chemoresistance in NSCLC cells at least partially by targeting PTEN.

  6. Lung cancer stem cells: An epigenetic perspective.

    PubMed

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

    2017-02-05

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

  7. Epigenetic regulation of ANKRD18B in lung cancer.

    PubMed

    Liu, Wen-Bin; Han, Fei; Jiang, Xiao; Yin, Li; Chen, Hong-Qiang; Li, Yong-Hong; Liu, Yong; Cao, Jia; Liu, Jin-Yi

    2015-04-01

    The identification of the key genetic and epigenetic changes underlying lung carcinogenesis would aid effective early diagnosis and targeted therapies for lung cancer. In this study, we screened a novel hypermethylated gene ankyrin repeat domain 18B (ANKRD18B), to determine whether it is regulated by DNA methylation and clarify its biological and clinical implications in lung cancer. Methylation status and expression level were analyzed by methylation-specific PCR, bisulfite genomic sequencing, and quantitative reverse transcription-polymerase chain reaction (qRT-PCR). We detected ANKRD18B hypermethylation in 52 of 98 (53.1%) primary lung cancer tissues and in nine of 10 (90%) cell lines, whereas no methylation was seen in 10 normal lung tissue samples. ANKRD18B methylation was more frequently observed in patients with poor differentiation (P < 0.05). Notably, 62 pairs of samples from patients whose tumor tissue showed hypermethylation of ANKRD18B exhibited the same aberrant methylation in 72.7% and 69.7% of their corresponding plasma and sputum samples, respectively; whereas no hypermethylation of ANKRD18B was detected in the sputum and plasma from patients whose tumor sample lacked this alteration. In addition, ANKRD18B mRNA expression was significantly decreased or silenced in lung cancer tissues and cell lines associated with hypermethylation of the ANKRD18B region. Demethylation agent 5-aza-2'-deoxycytidine significantly increased ANKRD18B mRNA expression in lung cancer cell lines. Furthermore, overexpression of ANKRD18B suppressed lung cancer cell growth. These results suggest that the expression of ANKRD18B is regulated by CpG island hypermethylation in lung cancer. Our findings confirm the importance of the identification of new markers of epigenetic dysregulation in cancer.

  8. Biomarkers of clinical benefit for anti-epidermal growth factor receptor agents in patients with non-small-cell lung cancer

    PubMed Central

    Pallis, A G; Fennell, D A; Szutowicz, E; Leighl, N B; Greillier, L; Dziadziuszko, R

    2011-01-01

    Non-small-cell lung cancer (NSCLC) remains by far the major cause of cancer-related death in the Western world in both men and women. The majority of patients will be diagnosed with metastatic disease, and chemotherapy doublets remain the cornerstone of treatment for these patients. However, chemotherapy has a minimal impact on long-term survival and prognosis remains poor for these patients. Further improvement in treatment is likely to require incorporation of novel targeted therapies. Among these agents, inhibitors of the epidermal growth factor receptor (EGFR) have demonstrated significant activity in the first-, second- or third-line treatment of NSCLC. The purpose of current paper is to present the evidence for using several proposed molecular biomarkers as a tool for selection of NSCLC patients for anti-EGFR treatment. According to current data, EGFR mutation status appears to be the strongest predictor for the selection of NSCLC patients to first-line treatment with EGFR tyrosine kinase inhibitors vs chemotherapy. Use of other biomarkers remains investigational. PMID:21654681

  9. Dichloroacetate alters Warburg metabolism, inhibits cell growth, and increases the X-ray sensitivity of human A549 and H1299 NSC lung cancer cells.

    PubMed

    Allen, Kah Tan; Chin-Sinex, Helen; DeLuca, Thomas; Pomerening, Joseph R; Sherer, Jeremy; Watkins, John B; Foley, John; Jesseph, Jerry M; Mendonca, Marc S

    2015-12-01

    We investigated whether altering Warburg metabolism (aerobic glycolysis) by treatment with the metabolic agent dichloroacetate (DCA) could increase the X-ray-induced cell killing of the radiation-resistant human non-small-cell lung cancer (NSCLC) cell lines A549 and H1299. Treatment with 50mM DCA decreased lactate production and glucose consumption in both A549 and H1299, clear indications of attenuated aerobic glycolysis. In addition, we found that DCA treatment also slowed cell growth, increased population-doubling time, and altered cell cycle distribution. Furthermore, we report that treatment with 50mM DCA significantly increased single and fractionated X-ray-induced cell killing of A549 and H1299 cells. Assay of DNA double-strand break repair by neutral comet assays demonstrated that DCA inhibited both the fast and the slow kinetics of X-ray-induced DSB repair in both A549 and H1299 NSCL cancer cells. Taken together the data suggest a correlation between an attenuated aerobic glycolysis and enhanced cytotoxicity and radiation-induced cell killing in radiation-resistant NSCLC cells.

  10. Cancer Stem Cells in Lung Tumorigenesis

    PubMed Central

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

    2011-01-01

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

  11. Lung cancer screening: the way forward

    PubMed Central

    Field, J K; Duffy, S W

    2008-01-01

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

  12. Lung Cancer - Multiple Languages: MedlinePlus

    MedlinePlus

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

  13. Lung Cancer Clinical Trials: Advances in Immunotherapy

    Cancer.gov

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

  14. Indoor radon and lung cancer in China

    SciTech Connect

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

    1990-06-20

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

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

    PubMed

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

    2003-10-01

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

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

    ClinicalTrials.gov

    2017-01-05

    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

  17. Progesterone receptor (PR) polyproline domain (PPD) mediates inhibition of epidermal growth factor receptor (EGFR) signaling in non-small cell lung cancer cells.

    PubMed

    Kawprasertsri, Sornsawan; Pietras, Richard J; Marquez-Garban, Diana C; Boonyaratanakornkit, Viroj

    2016-05-01

    Recent evidence has suggested a possible role for progesterone receptor (PR) in the progression of non-small cell lung cancer (NSCLC). However, little is known concerning roles of PR in NSCLC. PR contains a polyproline domain (PPD), which directly binds to the SH3 domain of signaling molecules. Because PPD-SH3 interactions are essential for EGFR signaling, we hypothesized that the presence of PR-PPD interfered with EGFR-mediated signaling and cell proliferation. We examined the role of PR-PPD in cell proliferation and signaling by stably expressing PR-B, or PR-B with disrupting mutations in the PPD (PR-BΔSH3), from a tetracycline-regulated promoter in A549 NSCLC cells. PR-B dose-dependently inhibited cell growth in the absence of ligand, and progestin (R5020) treatment further suppressed the growth. Treatment with RU486 abolished PR-B- and R5020-mediated inhibition of cell proliferation. Expression of PR-BΔSH3 and treatment with R5020 or RU486 had no effect on cell proliferation. Furthermore, PR-B expression but not PR-BΔSH3 expression reduced EGF-induced A549 proliferation and activation of ERK1/2, in the absence of ligand. Taken together, our data demonstrated the significance of PR extranuclear signaling through PPD interactions in EGFR-mediated proliferation and signaling in NSCLC.

  18. Drug delivery and nanodetection in lung cancer.

    PubMed

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

    2016-01-01

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

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

    PubMed Central

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

    2015-01-01

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

  20. Rubus idaeus L Inhibits Invasion Potential of Human A549 Lung Cancer Cells by Suppression Epithelial-to-Mesenchymal Transition and Akt Pathway In Vitro and Reduces Tumor Growth In Vivo.

    PubMed

    Chu, Shu-Chen; Hsieh, Yih-Shou; Hsu, Li-Sung; Chen, Kuo-Shuen; Chiang, Chien-Cheng; Chen, Pei-Ni

    2014-05-01

    The metastasis of lung cancer is the most prevalent cause of patient death. Various treatment strategies have targeted the prevention of the occurrence of metastasis. The epithelial-mesenchymal transition (EMT) in lung cancer cells is considered a prerequisite to acquire the invasive/migratory phenotype and to subsequently achieve metastasis. However, the effects ofRubus idaeuson cancer invasion and the EMT of the human lung carcinoma remain unclear. In this article, we test the hypothesis thatR idaeusethyl acetate (RIAE) possesses an antimetastatic effect and reverses the EMT potential of human lung A549 cells. We extract the raspberryR idaeuswith methanol (RIME), chloroform (RICE), ethyl acetate (RIAE),n-butanol (RIBE), and water (RIWE). The RIAE treatment obviously inhibits the invasive (P< .001), motility (P< .001), spreading, and migratory potential (P< .001) of highly metastatic human lung cancer A549 cells. The zymography and promoter luciferase analysis reveals that RIAE decreases the proteinase and transcription activities of MMP-2 and u-PA. Molecular analyses show that RIAE increases the E-cadherin level that is mainly localized at the cellular membrane. This result was also verified through confocal analyses. RIAE also induces the upregulation of an epithelial marker, such as α-catenin, and decreases mesenchymal markers, such as snail-1 and N-cadherin, that promote cell invasion and metastasis. RIAE inhibits MMP-2 and u-PA by attenuating the NF-κB and p-Akt expression. The inhibition of RIAE on the growth of A549 cells in vivo was also verified using a cancer cell xenograft nude mice model. Our results show the anti-invasive/antitumor effects of RIAE and associated mechanisms, which suggest that RIAE should be further tested in clinically relevant models to exploit its potential benefits against metastatic lung cancer cells.

  1. Screening for lung cancer: Does MRI have a role?

    PubMed

    Biederer, Juergen; Ohno, Yoshiharu; Hatabu, Hiroto; Schiebler, Mark L; van Beek, Edwin J R; Vogel-Claussen, Jens; Kauczor, Hans-Ulrich

    2017-01-01

    While the inauguration of national low dose computed tomographic (LDCT) lung cancer screening programs has started in the USA, other countries remain undecided, awaiting the results of ongoing trials. The continuous technical development achieved by stronger gradients, parallel imaging and shorter echo time has made lung magnetic resonance imaging (MRI) an interesting alternative to CT. For the detection of solid lesions with lung MRI, experimental and clinical studies have shown a threshold size of 3-4mm for nodules, with detection rates of 60-90% for lesions of 5-8mm and close to 100% for lesions of 8mm or larger. From experimental work, the sensitivity for infiltrative, non-solid lesions would be expected to be similarly high as that for solid lesions, but the published data for the MRI detection of lepidic growth type adenocarcinoma is sparse. Moreover, biological features such as a longer T2 time of lung cancer tissue, tissue compliance and a more rapid uptake of contrast material compared to granulomatous diseases, in principle should allow for the multi-parametric characterization of lung pathology. Experience with the clinical use of lung MRI is growing. There are now standardized protocols which are easy to implement on current scanner hardware configurations. The image quality has become more robust and currently ongoing studies will help to further contribute experience with multi-center, multi-vendor and multi-platform implementation of this technology. All of the required prerequisites have now been achieved to allow for a dedicated prospective large scale MRI based lung cancer screening trial to investigate the outcomes from using MRI rather than CT for lung cancer screening. This is driven by the hypothesis that MRI would reach a similarly high sensitivity for the detection of early lung cancer with fewer false positive exams (better specificity) than LDCT. The purpose of this review article is to discuss the potential role of lung MRI for the early

  2. Early diagnosis of lung cancer

    NASA Astrophysics Data System (ADS)

    Saccomanno, Geno; Bechtel, Joel J.

    1991-06-01

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

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

    ClinicalTrials.gov

    2016-11-07

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

  4. Early Lung Cancer Diagnosis by Biosensors

    PubMed Central

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

    2013-01-01

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

  5. HDAC10 promotes lung cancer proliferation via AKT phosphorylation

    PubMed Central

    Wang, Zhantong; Wang, Hsin-tzu; Duan, Baoyu; Ye, Dan; Wang, Chenxin; Jing, Ruiqi; Leng, Ye; Xi, Jiajie; Chen, Wen; Wang, Guiying; Jia, Wenwen; Zhu, Songcheng; Kang, Jiuhong

    2016-01-01

    Histone deacetylase 10 (HDAC10) is a member of the class II HDACs, and its role in cancer is emerging. In this study, we found that HDAC10 is highly expressed in lung cancer tissues. It resides mainly in the cytoplasm of lung cancer cells but resides in the nucleus of adjacent normal cells. Further examinations revealed that HDAC10 resides in the cytoplasm in multiple lung cancer cell lines, including the A549, H358 and H460 cell lines, but mainly resides in the nucleus of normal lung epithelial 16HBE cells. A leucine-rich motif, R505L506L507C508V509A510L511, was identified as its nuclear localization signal (NLS), and a mutant (Mut-505-511) featuring mutations to A at each of its original R and L positions was found to be nuclear-localization defective. Functional analysis revealed that HDAC10 promoted lung cancer cell growth and that its knockdown induced cell cycle arrest and apoptosis. Mechanistic studies showed that HDAC10 knockdown significantly decreased the phosphorylation of AKT at Ser473 and that AKT expression significantly rescued the cell cycle arrest and apoptosis elicited by HDAC10 knockdown. A co-immunoprecipitation assay suggested that HDAC10 interacts with AKT and that inhibition of HDAC10 activity decreases its interaction with and phosphorylation of AKT. Finally, we confirmed that HDAC10 promoted lung cancer proliferation in a mouse model. Our study demonstrated that HDAC10 localizes and functions in the cytoplasm of lung cancer cells, thereby underscoring its potential role in the diagnosis and treatment of lung cancer. PMID:27449083

  6. Cooperative cell-growth inhibition by combination treatment with ZD1839 (Iressa) and trastuzumab (Herceptin) in non-small-cell lung cancer.

    PubMed

    Nakamura, Hisashi; Takamori, Shinzo; Fujii, Teruhiko; Ono, Mayumi; Yamana, Hideaki; Kuwano, Michihiko; Shirouzu, Kazuo

    2005-12-08

    An important recent advance in anticancer therapy was the development of molecular-targeting drugs, such as the epidermal growth-factor receptor (EGFR)-targeting drug ZD1839 (Iressa) and the HER2-trageting anti-HER2 monoclonal antibody trastuzumab (Herceptin). ZD1839 and trastuzumab are reported to improve the therapeutic efficacy of treatment for non-small-cell lung cancer (NSCLC) and breast cancer, respectively, although the effectiveness of either drug alone is not satisfactory. NSCLC cells often express both EGFR and HER2. We therefore investigated whether a combination of ZD1839 and trastuzumab had an additive or synergistic antitumor effect. In culture ZD1839 inhibited the growth of four NSCLC cell lines (A549, NCI-H23, NCI-H727, and NCI-H661) that expressed various levels of EGFR, HER2, HER3, and HER4. A significant cytotoxic effect was observed when ZD1839 was combined with trastuzumab in A549 cells. However, this combination had no apparent effect in NCI-H23 cells. Significant G(1)-phase arrest, increased p27 expression and decreased cyclin E or D1 levels were detected in A549 cells treated with ZD1839 and trastuzumab. No significant effects were detected in NCI-H23 cells examined. The combination treatment significantly inhibited the phosphorylation of EGFR, HER2, retinoblastoma, extracellular signal-regulated kinase-1/2, and protein kinase B/Akt in A549 cells, but not in NCI-H23 cells. Our results indicated that increased levels of constitutive EGFR/HER2 heterodimers were formed in A549 cells in the presence of ZD1839, whereas no heterodimer formation was detected in NCI-H23 cells. We therefore suggest that combination treatment with ZD1839 and trastuzumab might have improved therapeutic efficacy against NSCLC cells expressing both EGFR and HER2.

  7. Nasal Swab Shows Promise in Confirming Lung Cancers

    MedlinePlus

    ... 163805.html Nasal Swab Shows Promise in Confirming Lung Cancers Simple technique is based on cancer DNA ... 27, 2017 MONDAY, Feb. 27, 2017 (HealthDay News) -- Lung cancer remains by far the leading cancer killer ...

  8. Genomic heterogeneity of multiple synchronous lung cancer

    PubMed Central

    Liu, Yu; Zhang, Jianjun; Li, Lin; Yin, Guangliang; Zhang, Jianhua; Zheng, Shan; Cheung, Hannah; Wu, Ning; Lu, Ning; Mao, Xizeng; Yang, Longhai; Zhang, Jiexin; Zhang, Li; Seth, Sahil; Chen, Huang; Song, Xingzhi; Liu, Kan; Xie, Yongqiang; Zhou, Lina; Zhao, Chuanduo; Han, Naijun; Chen, Wenting; Zhang, Susu; Chen, Longyun; Cai, Wenjun; Li, Lin; Shen, Miaozhong; Xu, Ningzhi; Cheng, Shujun; Yang, Huanming; Lee, J. Jack; Correa, Arlene; Fujimoto, Junya; Behrens, Carmen; Chow, Chi-Wan; William, William N.; Heymach, John V.; Hong, Waun Ki; Swisher, Stephen; Wistuba, Ignacio I.; Wang, Jun; Lin, Dongmei; Liu, Xiangyang; Futreal, P. Andrew; Gao, Yanning

    2016-01-01

    Multiple synchronous lung cancers (MSLCs) present a clinical dilemma as to whether individual tumours represent intrapulmonary metastases or independent tumours. In this study we analyse genomic profiles of 15 lung adenocarcinomas and one regional lymph node metastasis from 6 patients with MSLC. All 15 lung tumours demonstrate distinct genomic profiles, suggesting all are independent primary tumours, which are consistent with comprehensive histopathological assessment in 5 of the 6 patients. Lung tumours of the same individuals are no more similar to each other than are lung adenocarcinomas of different patients from TCGA cohort matched for tumour size and smoking status. Several known cancer-associated genes have different mutations in different tumours from the same patients. These findings suggest that in the context of identical constitutional genetic background and environmental exposure, different lung cancers in the same individual may have distinct genomic profiles and can be driven by distinct molecular events. PMID:27767028

  9. Radiation-induced lung damage promotes breast cancer lung-metastasis through CXCR4 signaling.

    PubMed

    Feys, Lynn; Descamps, Benedicte; Vanhove, Christian; Vral, Anne; Veldeman, Liv; Vermeulen, Stefan; De Wagter, Carlos; Bracke, Marc; De Wever, Olivier

    2015-09-29

    Radiotherapy is a mainstay in the postoperative treatment of breast cancer as it reduces the risks of local recurrence and mortality after both conservative surgery and mastectomy. Despite recent efforts to decrease irradiation volumes through accelerated partial irradiation techniques, late cardiac and pulmonary toxicity still occurs after breast irradiation. The importance of this pulmonary injury towards lung metastasis is unclear. Preirradiation of lung epithelial cells induces DNA damage, p53 activation and a secretome enriched in the chemokines SDF-1/CXCL12 and MIF. Irradiated lung epithelial cells stimulate adhesion, spreading, growth, and (transendothelial) migration of human MDA-MB-231 and murine 4T1 breast cancer cells. These metastasis-associated cellular activities were largely mimicked by recombinant CXCL12 and MIF. Moreover, an allosteric inhibitor of the CXCR4 receptor prevented the metastasis-associated cellular activities stimulated by the secretome of irradiated lung epithelial cells. Furthermore, partial (10%) irradiation of the right lung significantly stimulated breast cancer lung-specific metastasis in the syngeneic, orthotopic 4T1 breast cancer model.Our results warrant further investigation of the potential pro-metastatic effects of radiation and indicate the need to develop efficient drugs that will be successful in combination with radiotherapy to prevent therapy-induced spread of cancer cells.

  10. Radiation-induced lung damage promotes breast cancer lung-metastasis through CXCR4 signaling

    PubMed Central

    Feys, Lynn; Descamps, Benedicte; Vanhove, Christian; Vral, Anne; Veldeman, Liv; Vermeulen, Stefan; De Wagter, Carlos; Bracke, Marc; De Wever, Olivier

    2015-01-01

    Radiotherapy is a mainstay in the postoperative treatment of breast cancer as it reduces the risks of local recurrence and mortality after both conservative surgery and mastectomy. Despite recent efforts to decrease irradiation volumes through accelerated partial irradiation techniques, late cardiac and pulmonary toxicity still occurs after breast irradiation. The importance of this pulmonary injury towards lung metastasis is unclear. Preirradiation of lung epithelial cells induces DNA damage, p53 activation and a secretome enriched in the chemokines SDF-1/CXCL12 and MIF. Irradiated lung epithelial cells stimulate adhesion, spreading, growth, and (transendothelial) migration of human MDA-MB-231 and murine 4T1 breast cancer cells. These metastasis-associated cellular activities were largely mimicked by recombinant CXCL12 and MIF. Moreover, an allosteric inhibitor of the CXCR4 receptor prevented the metastasis-associated cellular activities stimulated by the secretome of irradiated lung epithelial cells. Furthermore, partial (10%) irradiation of the right lung significantly stimulated breast cancer lung-specific metastasis in the syngeneic, orthotopic 4T1 breast cancer model. Our results warrant further investigation of the potential pro-metastatic effects of radiation and indicate the need to develop efficient drugs that will be successful in combination with radiotherapy to prevent therapy-induced spread of cancer cells. PMID:26396176

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

    PubMed Central

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

    2014-01-01

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

  12. Lung Cancer in HIV-Infected Patients.

    PubMed

    Mena, Álvaro; Meijide, Héctor; Marcos, Pedro J

    2016-01-01

    The widespread use of HAART for persons living with HIV since 1996 has resulted in a dramatic decline in AIDS-related mortality. However, other comorbidities are increasing, such as metabolic disturbances or cancers, including solid organ malignancies. Among the latest, lung cancer, especially the adenocarcinoma subtype, is on the rise. HIV infection, even controlling for smoking, is an independent risk factor for developing lung cancer. HIV could promote lung cancers through immunosuppression, chronic inflammation, and a direct oncogenic effect. Smoking, lung infections, and chronic pulmonary diseases are risk factors for lung cancer. All may contribute to the cumulative incidence of lung cancer in persons living with HIV. It is double that in the general population. The role of HAART in lung cancer development in persons living with HIV is not well established. Although data supporting it could be too preliminary, persons living with HIV should be considered within high-risk groups that could benefit from screening strategies with low-dose computed tomography, especially those with airway obstruction and emphysema. Current evidence suggests that quitting smoking strategies in persons living with HIV achieve abstinence rates comparable to those in healthy HIV-negative smokers.

  13. Next-generation epidermal growth factor receptor tyrosine kinase inhibitors in epidermal growth factor receptor -mutant non-small cell lung cancer.

    PubMed

    Tan, Chee-Seng; Cho, Byoung-Chul; Soo, Ross A

    2016-03-01

    Since the discovery of sensitizing EGFR mutations as a predictive marker of sensitivity to EGFR tyrosine kinase inhibitors (TKIs), the field of targeted therapy in non-small cell lung cancer (NSCLC) has been revolutionized. Patients harbouring these sensitizing mutations treated with EGFR TKI have derived significant clinical outcome when compared with standard platinum based chemotherapy doublets. However disease progression invariably occurs at a median of about 9-13 months from initiation treatment, if acquired resistance commonly due to the development of EGFR T790M mutation. A novel class of "third generation" EGFR TKIs have been developed that is sensitising and T790M mutant-specific whilst sparing WT EGFR, representing a significant breakthrough in the treatment in NSCLC patients with acquired resistance harboring these genotypes. Early phase clinical data suggest the third generation EGFR TKIs such as osimertinib, rociletinib, and HM61713 are highly efficacious and well tolerated. Another promising class of EGFR TKI such as AZD3759 has been designed to penetrate blood brain barrier to treat brain metastases and leptomeningeal disease and has showed promising responses in patients with brain metastases. Acquired resistance to third generation EGFR TKIs has been reported including EGFR C797S. Given its non-invasive nature, plasma ctDNA is being explored as a possible approach to detect T790M mutation and to also inform on novel molecular mechansims of tertiary resistance to third generation EGFR TKIs. An understanding of the mechanisms of acquired resistance to the third-generation EGFR TKIs will greatly aid in the development of the next generation of EGFR TKIs.

  14. The liquid biopsy in lung cancer.

    PubMed

    Ansari, Junaid; Yun, Jungmi W; Kompelli, Anvesh R; Moufarrej, Youmna E; Alexander, Jonathan S; Herrera, Guillermo A; Shackelford, Rodney E

    2016-11-01

    The incidence of lung cancer has significantly increased over the last century, largely due to smoking, and remains the most common cause of cancer deaths worldwide. This is often due to lung cancer first presenting at late stages and a lack of curative therapeutic options at these later stages. Delayed diagnoses, inadequate tumor sampling, and lung cancer misdiagnoses are also not uncommon due to the limitations of the tissue biopsy. Our better understanding of the tumor microenvironment and the systemic actions of tumors, combined with the recent advent of the liquid biopsy, may allow molecular diagnostics to be done on circulating tumor markers, particularly circulating tumor DNA. Multiple liquid biopsy molecular methods are presently being examined to determine their efficacy as surrogates to the tumor tissue biopsy. This review will focus on new liquid biopsy technologies and how they may assist in lung cancer detection, diagnosis, and treatment.

  15. The liquid biopsy in lung cancer

    PubMed Central

    Ansari, Junaid; Yun, Jungmi W.; Kompelli, Anvesh R.; Moufarrej, Youmna E.; Alexander, Jonathan S.; Herrera, Guillermo A.; Shackelford, Rodney E.

    2016-01-01

    The incidence of lung cancer has significantly increased over the last century, largely due to smoking, and remains the most common cause of cancer deaths worldwide. This is often due to lung cancer first presenting at late stages and a lack of curative therapeutic options at these later stages. Delayed diagnoses, inadequate tumor sampling, and lung cancer misdiagnoses are also not uncommon due to the limitations of the tissue biopsy. Our better understanding of the tumor microenvironment and the systemic actions of tumors, combined with the recent advent of the liquid biopsy, may allow molecular diagnostics to be done on circulating tumor markers, particularly circulating tumor DNA. Multiple liquid biopsy molecular methods are presently being examined to determine their efficacy as surrogates to the tumor tissue biopsy. This review will focus on new liquid biopsy technologies and how they may assist in lung cancer detection, diagnosis, and treatment. PMID:28191282

  16. Detection of circulating vascular endothelial growth factor and matrix metalloproteinase-9 in non-small cell lung cancer using Luminex multiplex technology

    PubMed Central

    ZHANG, YE; WU, JIAN-ZHONG; ZHANG, JUN-YING; XUE, JING; MA, RONG; CAO, HAI-XIA; FENG, JI-FENG

    2014-01-01

    It has been previously reported that vascular endothelial growth factor (VEGF) and matrix metalloproteinase (MMP)-9 are important for the occurrence and development of non-small cell lung cancer (NSCLC). The present study was designed to detect the serum levels of VEGF and MMP-9 in NSCLC, and to explore their diagnostic and prognostic values. A total of 543 cases were involved, of which 332 were NSCLC (272 cases in the pretreatment group and 60 cases in the postoperative group), 91 were patients with benign lung diseases and 120 were healthy controls. The serum levels of VEGF and MMP-9 were determined by Luminex multiplex technology. The serum levels of VEGF and MMP-9 were found to be significantly higher in the pretreatment group than those in the patients with benign lung diseases and healthy controls (VEGF, P<0.0001; MMP-9, P<0.0001). Compared with the pretreatment group, the serum levels of VEGF and MMP-9 in the postoperative group were significantly decreased (VEGF, P=0.005; MMP-9, P=0.002), and the levels of VEGF and MMP-9 in the pretreatment group of patients with stages III and IV were higher than those with stages I and II (VEGF, P<0.0001; MMP-9, P=0.021). In addition, the levels of VEGF and MMP-9 were found to closely correlate with lymph node metastasis (VEGF, P<0.0001; MMP-9, P<0.0001) in the pretreatment group, while being independent of other clinicopathological parameters (P>0.05). Furthermore, a positive correlation was observed between the serum levels of VEGF and MMP-9 (r=0.159; P=0.009). A receiver operating characteristic curve analysis showed that the diagnostic value of MMP-9 was higher than that of VEGF in the pretreatment group. The log-rank test indicated that the inoperable NSCLC patients with low levels of VEGF exhibited a significantly longer overall survival time than those with high VEGF levels (P<0.0001). Additionally, the serum levels of VEGF and lymph node metastasis were identified as independent prognostic factors of the

  17. Prospective Study of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors Concurrent With Individualized Radiotherapy for Patients With Locally Advanced or Metastatic Non-Small-Cell Lung Cancer

    SciTech Connect

    Wang Jing; Xia Tingyi; Wang Yingjie; Li Hongqi; Li Ping; Wang Jidong; Chang Dongshu; Liu Liyyuan; Di Yupeng; Wang Xuan; Wu Weizhang

    2011-11-01

    Purpose: To establish the safety profile and efficacy of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) concurrent with individualized radiotherapy (RT) in patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC). Patients and Methods: Between June 2007 and January 2010, 26 patients with Stage III/IV NSCLC were enrolled in this prospective study. These patients were treated with EGFR-TKIs (gefitinib 250 mg or erlotinib 150 mg, oral daily) concurrent with individualized RT with curative intent. The thoracic RT plans were individually designed on the basis of tumor size and normal tissue volume constraints. All patients were assessed for toxicity, and 25 patients were available for efficacy. The primary endpoints were acute toxicity, overall survival, and median survival time. The secondary endpoints included local control rate, time to tumor progression, and progression-free survival (PFS). Results: Median gross tumor volume, mean lung dose, and lung V20 were 56 cm{sup 3}, 8.6 Gy, and 14%, respectively. Median thoracic radiation dose was 70 Gy at a margin of gross tumor volume (range, 42-82 Gy), and median biological equivalent dose was 105 Gy (range, 60-119 Gy). Acute skin, hematologic, esophageal, and pulmonary toxicities were acceptable and manageable. Severe adverse events included neutropenia (Grade 4, 4%) and thrombocytopenia (Grade 4, 8%), esophagitis (Grade 3, 4%), and pneumonitis (Grade 3, 4%). With a median follow-up of 10.2 months, a local control rate of 96% was achieved for thoracic tumor. Median time to progression, median PFS, and median survival time were 6.3, 10.2, and 21.8 months, respectively. The 1- and 2-year PFS rates were both 42%, and 1-, 2-, and 3-year overall survival rates were 57%, 45%, and 30%, respectively. Conclusion: Concurrent EGFR-TKIs with individualized RT shows a favorable safety profile and promising outcome, therefore serving as a therapeutic option for patients with locally

  18. MYCL is a target of a BET bromodomain inhibitor, JQ1, on growth suppression efficacy in small cell lung cancer cells

    PubMed Central

    Kato, Fuyumi; Fiorentino, Francesco Paolo; Alibés, Andreu; Perucho, Manuel; Sánchez-Céspedes, Montse; Kohno, Takashi; Yokota, Jun

    2016-01-01

    We aimed to elucidate the effect of JQ1, a BET inhibitor, on small cell lung cancers (SCLCs) with MYCL amplification and/or expression. Fourteen SCLC cell lines, including four with MYCL amplification, were examined for the effects of JQ1 on protein and gene expression by Western blot and mRNA microarray analyses. The sensitivity of SCLC cells to JQ1 was assessed by cell growth and apoptosis assays. MYCL was expressed in all the 14 cell lines, whereas MYC/MYCN expression was restricted mostly to cell lines with gene amplification. ASCL1, a transcription factor shown to play a role in SCLC, was also expressed in 11/14 cell lines. All SCLC cell lines were sensitive to JQ1 with GI50 values ≤1.23 μM, with six of them showing GI50 values <0.1 μM. Expression of MYCL as well as MYCN, ASCL1 and other driver oncogenes including CDK6 was reduced by JQ1 treatment, in particular in the cell lines with high expression of the respective genes; however, no association was observed between the sensitivity to JQ1 and the levels of MYCL, MYCN and ASCL1 expression. In contrast, levels of CDK6 expression and its reduction rates by JQ1 were associated with JQ1 sensitivity. Therefore, we concluded that CDK6 is a novel target of JQ1 and predictive marker for JQ1 sensitivity in SCLC cells. PMID:27764802

  19. Src-Family Kinases Are Activated in Non-Small Cell Lung Cancer and Promote the Survival of Epidermal Growth Factor Receptor-Dependent Cell Lines

    PubMed Central

    Zhang, Jie; Kalyankrishna, Shailaja; Wislez, Marie; Thilaganathan, Nishan; Saigal, Babita; Wei, Wei; Ma, Long; Wistuba, Ignacio I.; Johnson, Faye M.; Kurie, Jonathan M.

    2007-01-01

    The role of Src-family kinases (SFKs) in non-small cell lung cancer (NSCLC) has not been fully defined. Here we addressed this question by examining SFK phosphorylation in NSCLC biopsy samples and using genetic and pharmacological approaches to inhibit SFK expression and activity in cultured NSCLC cells. Immunohistochemical analysis of NSCLC biopsy samples using a Tyr416 phosphorylation-specific, pan-SFK antibody revealed staining in 123 (33%) of 370 tumors. Because c-Src is known to be both an upstream activator and downstream mediator of epidermal growth factor receptor (EGFR), we next investigated SFK phosphorylation in a panel of NSCLC cell lines, including ones that depend on EGFR for survival. The EGFR-dependent NSCLC cell lines HCC827 and H3255 had increased phosphorylation of SFKs, and treatment of these cells with an SFK inhibitor (PP1 or SKI-606) induced apoptosis. PP1 decreased phosphorylation of EGFR, ErbB2, and ErbB3 and strikingly enhanced apoptosis by gefitinib, an EGFR inhibitor. HCC827 cells transfected with c-Src short hairpin RNA exhibited diminished phosphorylation of EGFR and ErbB2 and decreased sensitivity to apoptosis by PP1 or gefitinib. We conclude that SFKs are activated in NSCLC biopsy samples, promote the survival of EGFR-dependent NSCLC cells, and should be investigated as therapeutic targets in NSCLC patients. PMID:17200208

  20. Advances in molecular-based personalized non-small-cell lung cancer therapy: targeting epidermal growth factor receptor and mechanisms of resistance

    PubMed Central

    Jotte, Robert M; Spigel, David R

    2015-01-01

    Molecularly targeted therapies, directed against the features of a given tumor, have allowed for a personalized approach to the treatment of advanced non-small-cell lung cancer (NSCLC). The reversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib had undergone turbulent clinical development until it was discovered that these agents have preferential activity in patients with NSCLC harboring activating EGFR mutations. Since then, a number of phase 3 clinical trials have collectively shown that EGFR-TKI monotherapy is more effective than combination chemotherapy as first-line therapy for EGFR mutation-positive advanced NSCLC. The next generation of EGFR-directed agents for EGFR mutation-positive advanced NSCLC is irreversible TKIs against EGFR and other ErbB family members, including afatinib, which was recently approved, and dacomitinib, which is currently being tested in phase 3 trials. As research efforts continue to explore the various proposed mechanisms of acquired resistance to EGFR-TKI therapy, agents that target signaling pathways downstream of EGFR are being studied in combination with EGFR TKIs in molecularly selected advanced NSCLC. Overall, the results of numerous ongoing phase 3 trials involving the EGFR TKIs will be instrumental in determining whether further gains in personalized therapy for advanced NSCLC are attainable with newer agents and combinations. This article reviews key clinical trial data for personalized NSCLC therapy with agents that target the EGFR and related pathways, specifically based on molecular characteristics of individual tumors, and mechanisms of resistance. PMID:26310719

  1. Biomarkers of response to epidermal growth factor receptor inhibitors in Non-Small-Cell Lung Cancer Working Group: standardization for use in the clinical trial setting.

    PubMed

    Eberhard, David A; Giaccone, Giuseppe; Johnson, Bruce E

    2008-02-20

    The body of literature on the correlations between molecular assessments and patient outcomes after treatment with epidermal growth factor receptor (EGFR) inhibitors continues to grow. It will be important in the future to determine how to most effectively integrate molecular assays that assess the likelihood of therapeutic benefit into clinical practice. Although EGFR-targeted therapies such as erlotinib have been approved for use without molecular testing, immunohistochemistry, fluorescence in situ hybridization, and mutational analyses of the EGFR gene have all been proposed as candidates to help predict response or survival benefit from EGFR-targeted therapy in patients with non-small-cell lung cancer (NSCLC). Further prospective validation from ongoing randomized studies will be needed to fully determine which assays are best to help predict patient outcome. In addition, it will be critical for these assays to undergo standardization before widespread clinical use. The Molecular Assays in NSCLC Working Group, under the sponsorship of Genentech Inc, Roche Pharmaceuticals, and OSI Pharmaceuticals, Inc, was convened to evaluate the available molecular assays for use in the clinical trial setting and provide recommendations for application and interpretation of these tests for future clinical trials. Recommendations of the Molecular Assays in NSCLC Working Group for the use of EGFR molecular assays are presented and include guidelines for tissue storage, handling, and processing. Recommendations for the standardization of molecular assays are also discussed.

  2. The Canadian Lung Cancer Conference 2016

    PubMed Central

    Melosky, B.; Ho, C.

    2016-01-01

    Each February, the Canadian Lung Cancer Conference brings together lung cancer researchers, clinicians, and care professionals who are united in their commitment to improve the care of patients with lung cancer. This year’s meeting, held 11–12 February, featured a resident education session, a welcome dinner, networking sessions, lectures, breakout sessions, debates, and a satellite symposium. Key themes from this year’s meeting included innovations across the care spectrum and results of recent clinical trials with targeted agents, immuno-oncology agents, and novel drug combinations.

  3. Bone metastasis from lung cancer identified by genetic profiling

    PubMed Central

    Liu, Zhu-Lin; Wang, Chun; Chen, Hui-Jiao; Li, Xue; Dai, Li-Jun; Ding, Zhen-Yu

    2017-01-01

    Cancer metastasis remains responsible for the vast majority of cases of cancer-related morbidity and mortality. Metastasis, by its definition, is the spread of cancer from the primary site to the distant tissues. Advancing the scientific and clinical understanding of cancer metastasis is a high priority. The prerequisite requirement for pathological consistency may be compromised during metastasis. The present study reports the case of a cancer patient with different pathological types. The patient presented with pain in the neck and right hip, as well as weight loss. He underwent whole-body positron emission tomography-computed tomography, which identified a mass in the lung and abnormal metabolism of the bone. Biopsies of the ilium and lung were performed and he was shown to have lung adenocarcinoma and bone squamous carcinoma. The morphology and immunohistochemical patterns were completely different, while each lesion harbored an identical genetic profile. The bone lesion was identified to be a metastasis from the lung cancer. The patient was prescribed an epithelial growth factor receptor inhibitor, which resulted in a partial response in the lung mass and alleviation of the patient's bone pain. Through this case study, we advocate the importance of using genetic testing in addition to pathological assessment. PMID:28356968

  4. Analysis of Expression of Vascular Endothelial Growth Factor A and Hypoxia Inducible Factor-1alpha in Patients Operated on Stage I Non-Small-Cell Lung Cancer

    PubMed Central

    Honguero Martínez, Antonio Francisco; Arnau Obrer, Antonio; Figueroa Almánzar, Santiago; León Atance, Pablo; Guijarro Jorge, Ricardo

    2014-01-01

    Objectives. Recent studies show that expression of hypoxia inducible factor-1alpha (HIF-1α) favours expression of vascular endothelial growth factor A (VEGF-A), and these biomarkers are linked to cellular proliferation, angiogenesis, and metastasis in different cancers. We analyze expression of HIF-1α and VEGF-A to clinicopathologic features and survival of patients operated on stage I non-small-cell lung cancer. Methodology. Prospective study of 52 patients operated on with stage I. Expression of VEGF-A and HIF-1α was performed through real-time quantitative polymerase chain reaction (qRT-PCR). Results. Mean age was 64.7 and 86.5% of patients were male. Stage IA represented 23.1% and stage IB 76.9%. Histology classification was 42.3% adenocarcinoma, 34.6% squamous cell carcinoma, and 23.1% others. Median survival was 81.0 months and 5-year survival 67.2%. There was correlation between HIF-1α and VEGF-A (P = 0.016). Patients with overexpression of HIF-1α had a tendency to better survival with marginal statistical significance (P = 0.062). Patients with overexpression of VEGF-A had worse survival, but not statistically significant (P = 0.133). Conclusion. The present study revealed that VEGF-A showed correlation with HIF-1α. HIF-1α had a tendency to protective effect with a P value close to statistical significance. VEGF-A showed a contrary effect but without statistical significance. PMID:26316946

  5. Understanding Mechanisms of Resistance in the Epithelial Growth Factor Receptor in Non-Small Cell Lung Cancer and the Role of Biopsy at Progression.

    PubMed

    Socinski, Mark A; Villaruz, Liza C; Ross, Jeffrey

    2017-01-01

    Molecular profiling and the discovery of drugs that target specific activating mutations have allowed the personalization of treatment for non-small cell lung cancer (NSCLC). The epithelial growth factor receptor (EGFR) is frequently over-expressed and/or aberrantly activated in different cancers, including NSCLC. The most common activating mutations of EGFR in NSCLC fall within the tyrosine kinase-binding domain. Three oral EGFR tyrosine kinase inhibitors (TKIs) have been approved by the U.S. Food and Drug Administration (FDA) for first-line use in patients with EGFR mutation-positive NSCLC (exon 19 deletions or exon 21 [L858R] substitution mutations), as detected by an FDA-approved test. However, disease progression is common and is often the result of secondary mutations, of which the EGFR T790M mutation is the most prevalent. Few options were available upon progression until the introduction of osimertinib, a kinase inhibitor that targets the T790M mutation, which was recently approved for use in patients with metastatic EGFR T790M mutation-positive NSCLC, as detected by an FDA-approved test, who progressed on or after EGFR TKI therapy. With the introduction of osimertinib, outcomes can now be improved in select patients. Therefore, performing a biopsy at progression to determine the underlying molecular cause of the acquired resistance is important for the enabling of individualized options that may provide the greatest opportunity for improved outcomes. This review discusses the latest updates in molecular testing at progression and outlines treatment options for this difficult-to-treat population.

  6. Fibroblast Growth Factor 2-A Predictor of Outcome for Patients Irradiated for Stage II-III Non-Small-Cell Lung Cancer

    SciTech Connect

    Rades, Dirk; Setter, Cornelia; Dahl, Olav; Schild, Steven E.; Noack, Frank

    2012-01-01

    Purpose: The prognostic value of the tumor cell expression of the fibroblast growth factor 2 (FGF-2) in patients with non-small-cell lung cancer (NSCLC) is unclear. The present study investigated the effect of tumor cell expression of FGF-2 on the outcome of 60 patients irradiated for Stage II-III NSCLC. Methods and Materials: The effect of FGF-2 expression and 13 additional factors on locoregional control (LRC), metastasis-free survival (MFS), and overall survival (OS) were retrospectively evaluated. These additional factors included age, gender, Karnofsky performance status, histologic type, histologic grade, T and N category, American Joint Committee on Cancer stage, surgery, chemotherapy, pack-years, smoking during radiotherapy, and hemoglobin during radiotherapy. Locoregional failure was identified by endoscopy or computed tomography. Univariate analyses were performed with the Kaplan-Meier method and the Wilcoxon test and multivariate analyses with the Cox proportional hazard model. Results: On univariate analysis, improved LRC was associated with surgery (p = .017), greater hemoglobin levels (p = .036), and FGF-2 negativity (p <.001). On multivariate analysis of LRC, surgery (relative risk [RR], 2.44; p = .037), and FGF-2 expression (RR, 5.06; p <.001) maintained significance. On univariate analysis, improved MFS was associated with squamous cell carcinoma (p = .020), greater hemoglobin levels (p = .007), and FGF-2 negativity (p = .001). On multivariate analysis of MFS, the hemoglobin levels (RR, 2.65; p = .019) and FGF-2 expression (RR, 3.05; p = .004) were significant. On univariate analysis, improved OS was associated with a lower N category (p = .048), greater hemoglobin levels (p <.001), and FGF-2 negativity (p <.001). On multivariate analysis of OS, greater hemoglobin levels (RR, 4.62; p = .002) and FGF-2 expression (RR, 3.25; p = .002) maintained significance. Conclusions: Tumor cell expression of FGF-2 appeared to be an independent negative predictor

  7. Molecular Mechanisms Underlying the Antitumor Activity of 3-Aminopropanamide Irreversible Inhibitors of the Epidermal Growth Factor Receptor in Non-Small Cell Lung Cancer1 2

    PubMed Central

    Galvani, Elena; Giovannetti, Elisa; Saccani, Francesca; Cavazzoni, Andrea; Leon, Leticia G; Dekker, Henk; Alfieri, Roberta; Carmi, Caterina; Mor, Marco; Ardizzoni, Andrea; Petronini, Pier Giorgio; Peters, Godefridus J

    2013-01-01

    Overcoming the emergence of acquired resistance to clinically approved epidermal growth factor receptor (EGFR) inhibitors is a major challenge in the treatment of advanced non-small cell lung cancer (NSCLC). The aim of this study was to investigate the effects of a series of novel compounds affecting viability of NSCLC NCI-H1975 cells (carrying the EGFR T790M mutation). The inhibition of the autophosphorylation of EGFR occurred at nanomolar concentrations and both UPR1282 and UPR1268 caused a significant induction of apoptosis. Targeting of EGFR and downstream pathways was confirmed by a peptide substrate array, which highlighted the inhibition of other kinases involved in NSCLC cell aggressive behavior. Accordingly, the drugs inhibited migration (about 30% vs. control), which could be, in part, explained also by the increase of E-cadherin expression. Additionally, we observed a contraction of the volume of H1975 spheroids, associated with the reduction of the cancer stem-like cell hallmark CD133. The activity of UPR1282 was retained in H1975 xenograft models where it determined tumor shrinkage (P < .05) and resulted well tolerated compared to canertinib. Of note, the kinase activity profile of UPR1282 on xenograft tumor tissues showed overlapping results with respect to the activity in H1975 cells, unraveling the inhibition of kinases involved in pivotal proliferation and invasive signaling pathways. In conclusion, UPR1282 and UPR1268 are effective against various processes involved in malignancy transformation and progression and may be promising compounds for the future treatment of gefitinib-resistant NSCLCs. PMID:23359111

  8. HuR-targeted nanotherapy in combination with AMD3100 suppresses CXCR4 expression, cell growth, migration and invasion in lung cancer.

    PubMed

    Muralidharan, R; Panneerselvam, J; Chen, A; Zhao, Y D; Munshi, A; Ramesh, R

    2015-12-01

    The CXCR4 chemokine receptor has an important role in cancer cell metastasis. The CXCR4 antagonist, AMD3100, has limited efficacy in controlling metastasis. HuR, an RNA-binding protein, regulates CXCR4 in cancer cells. We therefore investigated whether targeting HuR using a siRNA-based nanoparticle plus AMD3100 would suppress CXCR4 and inhibit lung cancer metastasis. We treated human H1299 lung cancer cells with HuR-specific siRNA contained in a folate-targeted lipid nanoparticle (HuR-FNP) plus AMD3100, and compared this with AMD3100 alone, HuR-FNP alone and no treatment. HuR-FNP plus AMD3100 treatment produced a G1 phase cell cycle arrest and reduced cell viability above and beyond the effects of AMD3100 alone. HuR and CXCR4 mRNA and protein expression levels were markedly reduced in all treatment groups. Phosphorylated (p) AKT(S473) protein was also reduced. P27 protein expression increased with HuR-FNP and combination treatment. Promoter-based reporter studies showed that the combination inhibited CXCR4 promoter activity more than did either treatment alone. Cell migration and invasion was significantly reduced with all treatments; the combination provided the most inhibition. Reduced matrix metalloprotease (MMP)-2 and -9 expression was associated with reduced invasion in all treatment groups. Thus, we found that combined HuR and CXCR4 targeting effectively controlled lung cancer metastasis.

  9. Missed lung cancer: when, where, and why?

    PubMed Central

    del Ciello, Annemilia; Franchi, Paola; Contegiacomo, Andrea; Cicchetti, Giuseppe; Bonomo, Lorenzo; Larici, Anna Rita

    2017-01-01

    Missed lung cancer is a source of concern among radiologists and an important medicolegal challenge. In 90% of the cases, errors in diagnosis of lung cancer occur on chest radiographs. It may be challenging for radiologists to distinguish a lung lesion from bones, pulmonary vessels, mediastinal structures, and other complex anatomical structures on chest radiographs. Nevertheless, lung cancer can also be overlooked on computed tomography (CT) scans, regardless of the context, either if a clinical or radiologic suspect exists or for other reasons. Awareness of the possible causes of overlooking a pulmonary lesion can give radiologists a chance to reduce the occurrence of this eventuality. Various factors contribute to a misdiagnosis of lung cancer on chest radiographs and on CT, often very similar in nature to each other. Observer error is the most significant one and comprises scanning error, recognition error, decision-making error, and satisfaction of search. Tumor characteristics such as lesion size, conspicuity, and location are also crucial in this context. Even technical aspects can contribute to the probability of skipping lung cancer, including image quality and patient positioning and movement. Albeit it is hard to remove missed lung cancer completely, strategies to reduce observer error and methods to improve technique and automated detection may be valuable in reducing its likelihood. PMID:28206951

  10. Oxytocin- and vasopressin-induced growth of human small-cell lung cancer is mediated by the mitogen-activated protein kinase pathway.

    PubMed

    Péqueux, C; Keegan, B P; Hagelstein, M-T; Geenen, V; Legros, J-J; North, W G

    2004-12-01

    Malignant growth of small-cell lung carcinoma is promoted by various neuroendocrine autocrine/paracrine loops. Therefore, to interfere with this mitogenic process, it is crucial to elucidate the mechanisms involved. It is known that the oxytocin (OT) and vasopressin (VP) genes, normally transcriptionally restricted in their expression, are activated in small-cell lung cancer (SCLC), concomitantly with expression of their receptors (OTR, V1aR, V1bR/V3R and V2R). The aim of the present study was to characterize, in concentrations close to physiological and pharmacological conditions, intracellular signalling events triggered by OT and VP binding to their specific receptors in SCLC cells and to identify factors mediating OT- and VP-induced mitogenic effects on SCLC. Known agonists for OTR ([Thr4,Gly7]OT) and V1aR (F180), in addition to OT and VP, were able to elicit increases in cytosolic Ca2+ levels and this effect could be blocked using an OTR antagonist (OVTA) or a V1aR antagonist (SR49059) respectively. There was no activation of the cAMP pathway detected after VP, dDAVP (a V2R agonist), or OT treatment. Stimulation of SCLC cells with OT and VP led to an increase of extracellular signal-regulated kinase (ERK) 1/2 phosphorylation, maximal at 5 min, and the subsequent phosphorylation of its downstream target p90 ribosomal S6 kinase (p90RSK). Pre-incubation with OVTA and SR49059, and with inhibitors of phospholipase C (PLC), protein kinase C (PKC), mitogen-activated protein kinase/ERK kinase (MEK) 1/2 and a Ca2+ chelator significantly reduced OT- and VP-induced ERK1/2 phosphorylations. OVTA, SR49059 as well as MEK1/2 and PKC inhibitors also downregulated OT- and VP-induced p90RSK phosphorylation. In [3H]thymidine-uptake experiments, we subsequently observed that PLC, Ca2+, PKC and ERK1/2 are absolutely required for the OT- and VP-stimulated SCLC cellular growth process. In conclusion, the results presented here indicate that OT- and VP-induced mitogenic effects on

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

    SciTech Connect

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

    2012-01-06

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

  12. Importance of Molecular Features of Non–Small Cell Lung Cancer for Choice of Treatment

    PubMed Central

    Moran, Cesar

    2011-01-01

    Lung cancer is the leading cause of cancer-related deaths in the United States. Approximately 85% of lung cancer is categorized as non–small cell lung cancer, and traditionally, non–small cell lung cancer has been treated with surgery, radiation, and chemotherapy. Targeted agents that inhibit the epidermal growth factor receptor pathway have been developed and integrated into the treatment regimens in non–small cell lung cancer. Currently, approved epidermal growth factor receptor inhibitors include the tyrosine kinase inhibitors erlotinib and gefitinib. Molecular determinants, such as epidermal growth factor receptor–activating mutations, have been associated with response to epidermal growth factor receptor tyrosine kinase inhibitors and may be used to guide treatment choices in patients with non–small cell lung cancer. Thus, treatment choice for patients with non–small cell lung cancer depends on molecular features of tumors; however, improved techniques are required to increase the specificity and efficiency of molecular profiling so that these methods can be incorporated into routine clinical practice. This review provides an overview of how genetic analysis is currently used to direct treatment choices in non–small cell lung cancer. PMID:21514411

  13. Metformin inhibits growth of human non-small cell lung cancer cells via liver kinase B-1-independent activation of adenosine monophosphate-activated protein kinase

    PubMed Central

    GUO, QIANQIAN; LIU, ZHIYAN; JIANG, LILI; LIU, MENGJIE; MA, JIEQUN; YANG, CHENGCHENG; HAN, LILI; NAN, KEJUN; LIANG, XUAN

    2016-01-01

    Metformin, the most widely administered oral anti-diabetic therapeutic agent, exerts its glucose-lowering effect predominantly via liver kinase B1 (LKB1)-dependent activation of adenosine monophosphate-activated protein kinase (AMPK). Accumulating evidence has demonstrated that metformin possesses potential antitumor effects. However, whether the antitumor effect of metformin is via the LKB1/AMPK signaling pathway remains to be determined. In the current study, the effects of metformin on proliferation, cell cycle progression, and apoptosis of human non-small cell lung cancer (NSCLC) H460 (LKB1-null) and H1299 (LKB1-positive) cells were assessed, and the role of LKB1/AMPK signaling in the anti-growth effects of metformin were investigated. Cell viability was determined using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, cell cycle distribution and apoptosis were assessed by flow cytometry, and protein expression levels were measured by western blotting. Metformin inhibited proliferation, induced significant cell cycle arrest at the G0–G1 phase and increased apoptosis in NSCLC cells in a time- and concentration-dependent manner, regardless of the level of LKB1 protein expression. Furthermore, knockdown of LKB1 with short hairpin RNA (shRNA) did not affect the antiproliferative effect of metformin in the H1299 cells. Metformin stimulated AMPK phosphorylation and subsequently suppressed the phosphorylation of mammalian target of rapamycin and its downstream effector, 70-kDa ribosomal protein S6 kinase in the two cell lines. These effects were abrogated by silencing AMPK with small interfering RNA (siRNA). In addition, knockdown of AMPK with siRNA inhibited the effect of metformin on cell proliferation in the two cell lines. These results provide evidence that the growth inhibition of metformin in NSCLC cells is mediated by LKB1-independent activation of AMPK, indicating that metformin may be a potential therapeutic agent for the treatment of

  14. RB loss in resistant EGFR mutant lung adenocarcinomas that transform to small-cell lung cancer

    PubMed Central

    Niederst, Matthew J.; Sequist, Lecia V.; Poirier, John T.; Mermel, Craig H.; Lockerman, Elizabeth L.; Garcia, Angel R.; Katayama, Ryohei; Costa, Carlotta; Ross, Kenneth N.; Moran, Teresa; Howe, Emily; Fulton, Linnea E.; Mulvey, Hillary E.; Bernardo, Lindsay A.; Mohamoud, Farhiya; Miyoshi, Norikatsu; VanderLaan, Paul A.; Costa, Daniel B.; Jänne, Pasi A.; Borger, Darrell R.; Ramaswamy, Sridhar; Shioda, Toshi; Iafrate, Anthony J.; Getz, Gad; Rudin, Charles M.; Mino-Kenudson, Mari; Engelman, Jeffrey A.

    2015-01-01

    Tyrosine kinase inhibitors are effective treatments for non-small-cell lung cancers (NSCLCs) with epidermal growth factor receptor (EGFR) mutations. However, relapse typically occurs after an average of 1 year of continuous treatment. A fundamental histological transformation from NSCLC to small-cell lung cancer (SCLC) is observed in a subset of the resistant cancers, but the molecular changes associated with this transformation remain unknown. Analysis of tumour samples and cell lines derived from resistant EGFR mutant patients revealed that Retinoblastoma (RB) is lost in 100% of these SCLC transformed cases, but rarely in those that remain NSCLC. Further, increased neuroendocrine marker and decreased EGFR expression as well as greater sensitivity to BCL2 family inhibition are observed in resistant SCLC transformed cancers compared with resistant NSCLCs. Together, these findings suggest that this subset of resistant cancers ultimately adopt many of the molecular and phenotypic characteristics of classical SCLC. PMID:25758528

  15. Addiction of lung cancer cells to GOF p53 is promoted by up-regulation of epidermal growth factor receptor through multiple contacts with p53 transactivation domain and promoter

    PubMed Central

    Vaughan, Catherine A.; Pearsall, Isabella; Singh, Shilpa; Windle, Brad; Deb, Swati P.; Grossman, Steven R.; Yeudall, W. Andrew; Deb, Sumitra

    2016-01-01

    Human lung cancers harboring gain-of-function (GOF) p53 alleles express higher levels of the epidermal growth factor receptor (EGFR). We demonstrate that a number of GOF p53 alleles directly upregulate EGFR. Knock-down of p53 in lung cancer cells lowers EGFR expression and reduces tumorigenicity and other GOF p53 properties. However, addiction of lung cancer cells to GOF p53 can be compensated by overexpressing EGFR, suggesting that EGFR plays a critical role in addiction. Chromatin immunoprecipitation (ChIP) using lung cancer cells expressing GOF p53 alleles showed that GOF p53 localized to the EGFR promoter. The sequence where GOF p53 is found to interact by ChIP seq can act as a GOF p53 response element. The presence of GOF p53 on the EGFR promoter increased histone H3 acetylation, indicating a mechanism whereby GOF p53 enhances chromatin opening for improved access to transcription factors (TFs). ChIP and ChIP-re-ChIP with p53, Sp1 and CBP histone acetylase (HAT) antibodies revealed docking of GOF p53 on Sp1, leading to increased binding of Sp1 and CBP to the EGFR promoter. Up-regulation of EGFR can occur via GOF p53 contact at other novel sites in the EGFR promoter even when TAD-I is inactivated; these sites are used by both intact and TAD-I mutated GOF p53 and might reflect redundancy in GOF p53 mechanisms for EGFR transactivation. Thus, the oncogenic action of GOF p53 in lung cancer is highly dependent on transactivation of the EGFR promoter via a novel transcriptional mechanism involving coordinated interactions of TFs, HATs and GOF p53. PMID:26820293

  16. [Lung cancer screening and management of small pulmonary nodules].

    PubMed

    Schulz, Christian

    2015-03-01

    Worldwide lung cancer is the leading cause of death from cancer. Most lung cancers are diagnosed at an advanced stage, so survival after lung cancer is generally poor. Diagnosis of lung cancer at earlier stages may be associated with an increased survival rate. This indicates that the implementation of lung cancer screening programs at the population level by means of low dose computed tomography might helpful to improve the outcome and mortality of lung cancer patients. By means of rapid advances in imaging technologies over the last decades it became possible to detect small lung nodules as small as a couple of millimeters. This recent developments require management algorithms to guide the clinical management of suspicious and indeterminate lung nodules found in computer tomography during lung cancer screening or by incidental finding.This review will focus on both, the recent advances in lung cancer screening and the guidelines for the management of small pulmonary nodules.

  17. Aptamer-hybrid nanoparticle bioconjugate efficiently delivers miRNA-29b to non-small-cell lung cancer cells and inhibits growth by downregulating essential oncoproteins

    PubMed Central

    Perepelyuk, Maryna; Maher, Christina; Lakshmikuttyamma, Ashakumary; Shoyele, Sunday A

    2016-01-01

    MicroRNAs (miRNAs) are potentially attractive candidates for cancer therapy. However, their therapeutic application is limited by lack of availability of an efficient delivery system to stably deliver these potent molecules intracellularly to cancer cells while avoiding healthy cells. We developed a novel aptamer-hybrid nanoparticle bioconjugate delivery system to selectively deliver miRNA-29b to MUC1-expressing cancer cells. Significant downregulation of oncoproteins DNMT3b and MCL1 was demonstrated by these MUC1 aptamer-functionalized hybrid nanoparticles in A549 cells. Furthermore, downregulation of these oncoproteins led to antiproliferative effect and induction of apoptosis in a superior version when compared with Lipofectamine 2000. This novel aptamer-hybrid nanoparticle bioconjugate delivery system could potentially serve as a platform for intracellular delivery of miRNAs to cancer cells, hence improving the therapeutic outcome of lung cancer. PMID:27555773

  18. Physical activity and lung cancer survivorship.

    PubMed

    Jones, Lee W

    2011-01-01

    A lung cancer diagnosis and associated therapeutic management is associated with unique and varying degrees of adverse physical/functional impairments that dramatically reduce a patient's ability to tolerate exercise. Poor exercise tolerance predisposes to increased susceptibility to other common age-related diseases, poor quality of life (QOL), and likely premature death. Here we review the putative literature investigating the role of exercise as an adjunct therapy across the lung cancer continuum (i.e., diagnosis to palliation). The current evidence suggests that exercise training is a safe and feasible adjunct therapy for operable lung cancer patients both before and after pulmonary resection. Among patients with inoperable disease, feasibility and safety studies of carefully prescribed exercise training are warranted. Preliminary evidence in this area supports that exercise therapy may be an important consideration in multidisciplinary management of patients diagnosed with lung cancer.

  19. Exercise therapy across the lung cancer continuum.

    PubMed

    Jones, Lee W; Eves, Neil D; Waner, Emily; Joy, Anil A

    2009-07-01

    A lung cancer diagnosis and associated therapeutic management are associated with unique and varying degrees of adverse physical/functional impairments that dramatically reduce patients' ability to tolerate exercise. Poor exercise capacity predisposes to increased susceptibility to other common age-related diseases, poor quality of life, and likely premature death. This article reviews the literature investigating the role of exercise as an adjunct therapy across the lung cancer continuum (ie, prevention to palliation). The current evidence suggests that exercise training is a safe and feasible adjunct therapy for patients with operable lung cancer both before and after pulmonary resection. Among patients with inoperable disease, feasibility and safety studies of carefully prescribed exercise training are warranted. Preliminary evidence in this area suggests that exercise therapy may be an important consideration in multidisciplinary management of patients diagnosed with lung cancer.

  20. Lung cancer in the Indian subcontinent

    PubMed Central

    Noronha, Vanita; Pinninti, Rakesh; Patil, Vijay M.; Joshi, Amit; Prabhash, Kumar

    2016-01-01

    Smoking tobacco, both cigarettes and beedis, is the principal risk factor for causation of lung cancer in Indian men; however, among Indian women, the association with smoking is not strong, suggesting that there could be other risk factors besides smoking. Despite numerous advances in recent years in terms of diagnostic methods, molecular changes, and therapeutic interventions, the outcomes of the lung cancer patients remain poor; hence, a better understanding of the risk factors may impact the preventive measures to be implemented at the community level. There is a lack of comprehensive data on lung cancer in India. In this review, we attempt to collate the available data on lung cancer from India. PMID:27606290

  1. Highly Sensitive Marker Panel for Guidance in Lung Cancer Rapid Diagnostic Units

    PubMed Central

    Blanco-Prieto, Sonia; De Chiara, Loretta; Rodríguez-Girondo, Mar; Vázquez-Iglesias, Lorena; Rodríguez-Berrocal, Francisco Javier; Fernández-Villar, Alberto; Botana-Rial, María Isabel; de la Cadena, María Páez

    2017-01-01

    While evidence for lung cancer screening implementation in Europe is awaited, Rapid Diagnostic Units have been established in many hospitals to accelerate the early diagnosis of lung cancer. We seek to develop an algorithm to detect lung cancer in a symptomatic population attending such unit, based on a sensitive serum marker panel. Serum concentrations of Epidermal Growth Factor, sCD26, Calprotectin, Matrix Metalloproteinases −1, −7, −9, CEA and CYFRA 21.1 were determined in 140 patients with respiratory symptoms (lung cancer and controls with/without benign pathology). Logistic Lasso regression was performed to derive a lung cancer prediction model, and the resulting algorithm was tested in a validation set. A classification rule based on EGF, sCD26, Calprotectin and CEA was established, able to reasonably discriminate lung cancer with 97% sensitivity and 43% specificity in the training set, and 91.7% sensitivity and 45.4% specificity in the validation set. Overall, the panel identified with high sensitivity stage I non-small cell lung cancer (94.7%) and 100% small-cell lung cancers. Our study provides a sensitive 4-marker classification algorithm for lung cancer detection to aid in the management of suspicious lung cancer patients in the context of Rapid Diagnostic Units. PMID:28117344

  2. Immunotherapy for lung cancer: advances and prospects

    PubMed Central

    Yang, Li; Wang, Liping; Zhang, Yi

    2016-01-01

    Lung cancer is the most commonly diagnosed cancer as well as the leading cause of cancer-related deaths worldwide. To date, surgery is the first choice treatment, but most clinically diagnosed cases are inoperable. While chemotherapy and/or radiotherapy are the next considered options for such cases, these treatment modalities have adverse effects and are sometimes lethal to patients. Thus, new effective strategies with minimal side effects are urgently needed. Cancer immunotherapy provides either active or passive immunity to target tumors. Multiple immunotherapy agents have been proposed and tested for potential therapeutic benefit against lung cancer, and some pose fewer side effects as compared to conventional chemotherapy and radiotherapy. In this article, we discuss studies focusing on interactions between lung cancer and the immune system, and we place an emphasis on outcome evidence in order to create a knowledge base well-grounded in clinical reality. Overall, this review highlights the need for new lung cancer treatment options, with much ground to be paved for future advances in the field. We believe that immunotherapy agents alone or with other forms of treatment can be recognized as next modality of lung cancer treatment. PMID:27168951

  3. Repression of phosphoinositide-dependent protein kinase 1 expression by ciglitazone via Egr-1 represents a new approach for inhibition of lung cancer cell growth

    PubMed Central

    2014-01-01

    Background Peroxisome proliferator-activated receptors gamma (PPARγ) ligands have been shown to inhibit the growth of non-small cell lung cancer (NSCLC) cells. However, the mechanisms underlying this effect remain incompletely elucidated. Methods Cell proliferation and apoptosis were measured by cell viability, MTT and caspase3/7 activity assays. Phosphorylation/protein expression and gene silence/overexpression of AMPKα, phosphoinositide-dependent protein kinase 1 (PDK1), Egr-1 and PPARγ were performed by Western blot and siRNA/transfection assays. Dual-Luciferase Reporter Kit was used to measure the PPAR response elements (PPRE) reporter and PDK1 promoter activities, and ChIP assay was used to detect the Egr-1 protein binding to the DNA site in the PDK1 gene promoter. Results We found that ciglitazone, one synthetic PPARγ ligand, inhibited growth and induced apoptosis of NSCLC cells through decreased expression of PDK1, which was not blocked by GW9662 (a specific PPARγ antagonist). Overexpression of PDK1 overcame the effect of ciglitazone on cell growth and caspase 3/7 activity. Ciglitazone increased the phosphorylation of AMPKα and c-Jun N-terminal kinase (JNK), and the inhibitor of AMPK (compound C), but not JNK (SP600125), reversed the effect of ciglitazone on PDK1 protein expression. Ciglitazone reduced PDK1 gene promoter activity, which was not observed in cells exposed to compound C, but not silenced of PPARγ siRNA. Combination of ciglitazone and metformin further reduced PDK1 expression and promoter activity. Furthermore, we showed that ciglitazone induced the protein expression of Egr-1, which was not observed in cells silencing of AMPKα. Moreover, silencing of Egr-1 abrogated the effect of ciglitazone on PDK1 promoter activity and cell growth. On the contrary, overexpression of Egr-1 enhanced the effect of ciglitazone on PDK1 gene promoter activity. ChIP assays demonstrated that ciglitazone induced Egr-1 protein bind to the specific DNA site

  4. Utility and applications of orthotopic models of human non-small cell lung cancer (NSCLC) for the evaluation of novel and emerging cancer therapeutics.

    PubMed

    Justilien, Verline; Fields, Alan P

    2013-10-08

    Lung cancer is a leading cause of cancer deaths worldwide. Despite advances in chemotherapy, radiation therapy, and surgery, lung cancer continues to have a low 5-year survival rate, highlighting a dire need for more effective means of prevention, diagnosis, prognosis, and treatment. Mouse models that recapitulate the clinical features of advanced human lung cancer are critical for testing novel therapeutic approaches. This unit describes a highly reproducible, easy-to-establish orthotopic murine model of lung cancer, provides methods for in vivo imaging and monitoring of tumor growth, and discusses the usefulness of this model for translational lung cancer research and the development of therapeutic strategies.

  5. Nutrition, growth, and cancer

    SciTech Connect

    Tryfiates, G.P. )

    1988-01-01

    This book contains 26 papers. Some of the titles are: Defects in early and late stages of nucleotide excision repair and the origins of cancer; Mutagenesis, carcinogenesis, and the metal elements - DNA interaction; An overview of the role of diet and nutrition in carcinogenesis; Dietary modifiers in cancer; and Factors influencing glia growth in culture: Nutrients and cell-secreted factors.

  6. Lung Cancers Diagnosed at Annual CT Screening: Volume Doubling Times

    PubMed Central

    Yankelevitz, David F.; Yip, Rowena; Reeves, Anthony P.; Farooqi, Ali; Xu, Dongming; Smith, James P.; Libby, Daniel M.; Pasmantier, Mark W.; Miettinen, Olli S.

    2012-01-01

    Purpose: To empirically address the distribution of the volume doubling time (VDT) of lung cancers diagnosed in repeat annual rounds of computed tomographic (CT) screening in the International Early Lung Cancer Action Program (I-ELCAP), first and foremost with respect to rates of tumor growth but also in terms of cell types. Materials and Methods: All CT screenings in I-ELCAP from 1993 to 2009 were performed according to HIPAA-compliant protocols approved by the institutional review boards of the collaborating institutions. All instances of first diagnosis of primary lung cancer after a negative screening result 7–18 months earlier were identified, with symptom-prompted diagnoses included. Lesion diameter was calculated by using the measured length and width of each cancer at the time when the nodule was first identified for further work-up and at the time of the most recent prior screening, 7–18 months earlier. The length and width were measured a second time for each cancer, and the geometric mean of the two calculated diameters was used to calculate the VDT. The χ2 statistic was used to compare the VDT distributions. Results: The median VDT for 111 cancers was 98 days (interquartile range, 108). For 56 (50%) cancers it was less than 100 days, and for three (3%) cancers it was more than 400 days. Adenocarcinoma was the most frequent cell type (50%), followed by squamous cell carcinoma (19%), small cell carcinoma (19%), and others (12%). Lung cancers manifesting as subsolid nodules had significantly longer VDTs than those manifesting as solid nodules (P < .0001). Conclusion: Lung cancers diagnosed in annual repeat rounds of CT screening, as manifest by the VDT and cell-type distributions, are similar to those diagnosed in the absence of screening. © RSNA, 2012 PMID:22454506

  7. Green tea and prevention of esophageal and lung cancers.

    PubMed

    Yuan, Jian-Min

    2011-06-01

    Green tea contains high concentrations of tea polyphenols that have shown inhibitory effects against the development, progress, and growth of carcinogen-induced tumors in animal models at different organ sites, including the esophagus and lung. Green tea polyphenols also have shown to suppress cell proliferation and induce apoptosis. Besides antioxidative property, green tea polyphenols have pro-oxidative activities under certain conditions and modulate phase II metabolic enzymes that can enhance the detoxification pathway of environmental toxicants and carcinogens. Although epidemiological studies have provided inconclusive results on the effect of green tea consumption against the development of esophageal and lung cancers in humans overall, the inverse association between green tea intake and risk of esophageal cancer risk is more consistently observed in studies with adequate control for potential confounders. Epidemiological studies also have demonstrated an inverse, albeit moderate, association between green tea consumption and lung cancer, especially in non-smokers. This article reviews data on the cancer-preventive activities of green tea extract and green tea polyphenols and possible mechanisms against the esophageal and lung carcinogenesis in experimental animals, and summarizes the current knowledge from epidemiological studies on the relationship between green tea consumption and esophageal and lung cancer risk in humans.

  8. Exhaled breath analysis for lung cancer

    PubMed Central

    Sutedja, Tom G.; Zimmerman, Paul V.

    2013-01-01

    Early diagnosis of lung cancer results in improved survival compared to diagnosis with more advanced disease. Early disease is not reliably indicated by symptoms. Because investigations such as bronchoscopy and needle biopsy have associated risks and substantial costs, they are not suitable for population screening. Hence new easily applicable tests, which can be used to screen individuals at risk, are required. Biomarker testing in exhaled breath samples is a simple, relatively inexpensive, non-invasive approach. Exhaled breath contains volatile and non-volatile organic compounds produced as end-products of metabolic processes and the composition of such compounds varies between healthy subjects and subjects with lung cancer. Many studies have analysed the patterns of these compounds in exhaled breath. In addition studies have also reported that the exhaled breath condensate (EBC) can reveal gene mutations or DNA abnormalities in patients with lung cancer. This review has summarised the scientific evidence demonstrating that lung cancer has distinct chemical profiles in exhaled breath and characteristic genetic changes in EBC. It is not yet possible to accurately identify individuals with lung cancer in at risk populations by any of these techniques. However, analysis of both volatile organic compounds in exhaled breath and of EBC have great potential to become clinically useful diagnostic and screening tools for early stage lung cancer detection. PMID:24163746

  9. Lung Cancer Screening with Low Dose CT

    PubMed Central

    Caroline, Chiles

    2014-01-01

    SUMMARY The announcement of the results of the NLST, showing a 20% reduction in lung-cancer specific mortality with LDCT screening in a high risk population, marked a turning point in lung cancer screening. This was the first time that a randomized controlled trial had shown a mortality reduction with an imaging modality aimed at early detection of lung cancer. Current guidelines endorse LDCT screening for smokers and former smokers ages 55 to 74, with at least a 30 pack year smoking history. Adherence to published algorithms for nodule follow-up is strongly encouraged. Future directions for screening research include risk stratification for selection of the screening population, and improvements in the diagnostic follow-up for indeterminate pulmonary nodules. As with screening for other malignancies, screening for lung cancer with LDCT has revealed that there are indolent lung cancers which may not be fatal. More research is necessary if we are to maximize the risk-benefit ratio in lung cancer screening. PMID:24267709

  10. Clinical characteristics and response to tyrosine kinase inhibitors of patients with non-small cell lung cancer harboring uncommon epidermal growth factor receptor mutations

    PubMed Central

    Zhang, Yan; Wang, Zheng; Hao, Xuezhi; Hu, Xingsheng; Wang, Hongyu; Wang, Yan; Ying, Jianming

    2017-01-01

    Objective To investigate the clinical features of patients with non-small cell lung cancer (NSCLC) harboring uncommon epidermal growth factor receptor (EGFR) mutations, and the treatment outcomes of EGFR tyrosine kinase inhibitors (TKIs) in these patients. Methods We retrospectively analyzed the data of 128 NSCLC patients pathologically diagnosed with uncommon EGFR mutation in the Department of Pathology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College and Beijing Hospital from January 2010 to December 2015, including 40 advanced patients who received EGFR-TKI. Results Among the total 128 patients, 11 patients were non-adenocarcinoma, including squamous carcinoma (3.9%), adenosquamous carcinoma (2.3%), large cell carcinoma (0.8%), and composite neuroendocrine carcinoma (1.6%). Single mutations accounted for 75.0% (96/128), including G719X (29.7%), S768I (18.0%), 20 exon insertion (13.3%), L861Q (12.5%),De novo T790M (0.8%), and T725 (0.8%). Thirty-two patients harbored complex mutations. Forty advanced patients received EGFR-TKI, the objective response rate (ORR) was 20.0%, the disease control rate (DCR) was 85.0%, and the progression-free survival (PFS) was 6.4 [95% confidence interval (95% CI), 4.8–7.9] months. The exploratory analysis of tumor response and PFS in 33 patients with G719X/S768I/L861Q subtypes showed that ORR was 21.2% (7/33), the DCR was 93.9% (31/33), and PFS was 7.6 (95% CI, 5.8–9.4) months. Patients with exon 20 insertion mutation andDe novo T790M experienced rapid disease progression with PFS no more than 2.7 months. Conclusions Uncommon EGFR-mutant NSCLCs are heterogeneous, EGFR-TKIs can have different efficacy in this specific subtype, and thus further individual assessment is required for each case. PMID:28373750

  11. Good clinical response to gefitinib in a non-small cell lung cancer patient harboring a rare somatic epidermal growth factor gene point mutation; codon 768 AGC > ATC in exon 20 (S768I).

    PubMed

    Masago, Katsuhiro; Fujita, Shiro; Irisa, Kaoru; Kim, Yung Hak; Ichikawa, Masataka; Mio, Tadashi; Mishima, Michiaki

    2010-11-01

    Recently, two small-molecule kinase inhibitors targeting epidermal growth factor receptor have proven effective in the treatment of non-small cell lung cancer. There are specific activating mutations within the tyrosine kinase domain of epidermal growth factor receptor related to the sensitivity of tyrosine kinase inhibitors. However, it is unknown whether rare mutations in the N-lobe (exons 18-20) and the C-lobe (exon 21) of the epidermal growth factor receptor kinase domain other than L858R in exon 21 and the in-frame deletion in exon 19 may predict the effectiveness of epidermal growth factor receptor-tyrosine kinase inhibitors. We reported a case of non-small cell lung cancer harboring a rare epidermal growth factor somatic mutation, codon 768 AGC > ATC in exon 20 (S768I), who showed a good clinical response to gefitinib. Therefore, we may suggest that this rare mutation (S768I in exon 20) may not be an insensitive epidermal growth factor receptor somatic mutation in vivo.

  12. Indoor radon and lung cancer in China.

    PubMed

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

    1990-06-20

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

  13. The early diagnosis of lung cancer

    PubMed Central

    Deeley, T. J.

    1972-01-01

    Earlier diagnosis of malignant disease in the lung may bring about improvements in the treatment. This article discusses the effects of early diagnosis on the prognosis. Cancer of the lung may be associated with other lung pathology, thus increasing the problems of diagnosis. Diagnosis depends on radiological examination, cytology of the sputum, radio-isotope lung scanning and mediastinoscopy: an account is given of how these may be used to diagnose the condition whilst it is still at an early stage and suitable for radical treatment. PMID:4552427

  14. Long-term survival of a patient with lung cancer metastasis to the spine following surgical treatment combined with radiation and epithelial growth factor receptor inhibitor therapy: A case report

    PubMed Central

    XU, SONGFENG; YU, XIUCHUN; XU, MING

    2015-01-01

    The prognosis of patients with lung cancer metastasis to the spine is poor, and the choice of surgery is questionable based on the aggressiveness of the disease. The present study describes a case of a 56-year-old male with metastatic spinal cord compression. The patient underwent surgery for posterior decompression and internal fixation, in addition to receiving postoperative radiation and epidermal growth factor receptor (EGFR) inhibitor medication. After 24 months, positron emission tomography-computed tomography scan showed a reduction in the left upper lobe mass in the short axis and inactivation of the neoplasm in the left upper lobe and T9 vertebra. Based on these promising results, it is suggested that orthopedic oncologists consider the combination of radiation and EGFR inhibitor therapy with surgery for the treatment of lung cancer metastasis to the spine. PMID:25452785

  15. Mineral particles, mineral fibers, and lung cancer

    SciTech Connect

    Churg, A.; Wiggs, B.

    1985-08-01

    The total fibrous and nonfibrous mineral content of the lung has been analyzed in a series of 14 men with lung cancer but no history of occupational dust exposure, and in a series of 14 control men matched for age, smoking history, and general occupational class. The lung cancer patients had an average of 525 +/- 369 X 10(6) exogenous mineral particles and 17.4 +/- 19.6 X 10(6) exogenous mineral fibers/g dry lung, while the controls had averages of 261 +/- 175 mineral particles and 4.7 +/- 3.2 X 10(6) mineral fibers/g dry lung. These differences are statistically significant for both particles and fibers. Kaolinite, talc, mica, feldspars, and crystalline silica comprised the majority of particles of both groups. Approximately 90% of the particles were smaller than 2 micron in diameter and approximately 60% smaller than 1 micron. In both groups, patients who had smoked more than 35 pack years had greater numbers of particles than patients who had smoked less than 35 pack years. It is concluded that, in this study, lungs from patients with lung cancer had statistically greater numbers of mineral particles and fibers than lungs from controls, and that smoking influences total long-term retention of particles from all sources.

  16. Acyl-Coenzyme A Binding Protein Regulates Beta Oxidation Required for Growth and Survival of Non-Small Cell Lung Cancer

    PubMed Central

    Harris, Fredrick T.; Rahman, S.M. Jamshedur; Hassanein, Mohamed; Qian, Jun; Hoeksema, Megan D.; Chen, Heidi; Eisenberg, Rosana; Chaurand, Pierre; Caprioli, Richard M.; Shiota, Masakazu; Massion, Pierre P.

    2014-01-01

    We identified Acyl-Coenzyme A Binding Protein (ACBP) as part of a proteomic signature predicting the risk of having lung cancer. Because ACBP is known to regulate beta oxidation (β-oxidation), which in turn controls cellular proliferation, we hypothesized that ACBP contributes to regulation of cellular proliferation and survival of non-small cell lung cancer (NSCLC) by modulating β-oxidation. We utilized matrix assisted laser desorption ionization- imaging mass spectrometry (MALDI-IMS) and immunohistochemistry (IHC) to confirm ACBP’s tissue localization in pre-invasive and invasive NSCLCs. We correlated ACBP gene expression levels in NSCLC with clinical outcomes. In loss of function studies, we tested the effect of the downregulation of ACBP on cellular proliferation and apoptosis in normal bronchial and NSCLC cell lines. Using tritiated-palmitate (3H-palmitate), we measured β-oxidation levels and tested the effect of etomoxir, a β-oxidation inhibitor, on proliferation and apoptosis. MALDI-IMS and IHC analysis confirmed that ACBP is overexpressed in preinvasive and invasive lung cancers. High ACBP gene expression levels in NSCLCs correlated with worse survival (HR = 1.73). We observed a 40% decrease in β-oxidation and concordant decreases in proliferation and increases in apoptosis in ACBP depleted NSCLC cells as compared to bronchial airway epithelial cells. Inhibition of β-oxidation by etomoxir in ACBP overexpressing cells produced dose-dependent decrease in proliferation, and increase in apoptosis (p=0.01 and p <0.001 respectively). These data suggest a role for ACBP in controlling lung cancer progression by regulating β-oxidation. PMID:24819876

  17. Low local blood perfusion, high white blood cell and high platelet count are associated with primary tumor growth and lung metastasis in a 4T1 mouse breast cancer metastasis model.

    PubMed

    Wang, Chuan; Chen, Ying-Ge; Gao, Jian-Li; Lyu, Gui-Yuan; Su, Jie; Zhang, Q I; Ji, Xin; Yan, Ji-Zhong; Qiu, Qiao-Li; Zhang, Yue-Li; Li, Lin-Zi; Xu, Han-Ting; Chen, Su-Hong

    2015-08-01

    It was originally thought that no single routine blood test result would be able to indicate whether or not a patient had cancer; however, several novel studies have indicated that the median survival and prognosis of cancer patients were markedly associated with the systemic circulation features of cancer patients. In addition, certain parameters, such as white blood cell (WBC) count, were largely altered in malignant tumors. In the present study, routine blood tests were performed in order to observe the change of blood cells in tumor-bearing mice following the implantation of 4T1 breast cancer cells into the mammary fat pad; in addition, blood flow in breast tumor sites was measured indirectly using laser Doppler perfusion imaging (LDPI), in an attempt to explain the relevance between the blood circulation features and the growth or metastasis of breast cancer in mice model. The LDPI and blood test results indicated that the implantation of 4T1 breast cancer cells into BALB/c mice led to thrombosis as well as high WBC count, high platelet count, high plateletcrit and low blood perfusion. Following implantation of the 4T1 cells for four weeks, the lung metastatic number was determined and the Pearson correlation coefficient revealed that the number of visceral lung metastatic sites had a marked negative association with the ratio of basophils (BASO%; r=-0.512; P<0.01) and the mean corpuscular hemoglobin was significantly correlated with primary tumor weight (r=0.425; P<0.05). In conclusion, the results of the present study demonstrated that tumor growth led to thrombosis and acute anemia in mice; in addition, when blood BASO% was low, an increased number of lung metastases were observed in tumor-bearing mice.

  18. Reactivation of epigenetically silenced miR-512 and miR-373 sensitizes lung cancer cells to cisplatin and restricts tumor growth

    PubMed Central

    Adi Harel, S; Bossel Ben-Moshe, N; Aylon, Y; Bublik, D R; Moskovits, N; Toperoff, G; Azaiza, D; Biagoni, F; Fuchs, G; Wilder, S; Hellman, A; Blandino, G; Domany, E; Oren, M

    2015-01-01

    MicroRNAs (miRs) regulate a variety of cellular processes, and their impaired expression is involved in cancer. Silencing of tumor-suppressive miRs in cancer can occur through epigenetic modifications, including DNA methylation and histone deacetylation. We performed comparative miR profiling on cultured lung cancer cells before and after treatment with 5′aza-deoxycytidine plus Trichostatin A to reverse DNA methylation and histone deacetylation, respectively. Several tens of miRs were strongly induced by such ‘epigenetic therapy'. Two representatives, miR-512-5p (miR-512) and miR-373, were selected for further analysis. Both miRs were secreted in exosomes. Re-expression of both miRs augmented cisplatin-induced apoptosis and inhibited cell migration; miR-512 also reduced cell proliferation. TEAD4 mRNA was confirmed as a direct target of miR-512; likewise, miR-373 was found to target RelA and PIK3CA mRNA directly. Our results imply that miR-512 and miR-373 exert cell-autonomous and non-autonomous tumor-suppressive effects in lung cancer cells, where their re-expression may benefit epigenetic cancer therapy. PMID:25591738

  19. [The new TNM classification in lung cancer].

    PubMed

    Wrona, Anna; Jassem, Jacek

    2010-01-01

    This paper presents the new TNM classification in lung cancer and its history. Seventh edition of tumor, node, metastasis (TNM) classification in lung cancer has been published by the International Union Against Cancer (UICC) and the American Joint Committee on Cancer (AJCC) at the beginning of 2009. The changes were based upon the results of the international project of the International Association for the Study of Lung Cancer (IASLC). The database included 81.495 patients from the entire world (68.463 with non-small cell lung cancer and 13.032 with small cell lung cancer) treated with various modalities between 1990 and 2000. The collected data were validated internally and externally. The tumor size was considered of prognostic relevance: T1 tumors were subdivided into T1a (≤ 2 cm) and T1b (〉 2 cm - ≤ 3 cm), T2 tumors into T2a (〉 3 cm - ≤ 5 cm) and T2b (〉 5 cm - ≤ 7 cm), and T2 tumors 〉 7 cm were reclassified as T3. Tumors with the additional nodules in the same lobe as the primary tumor were classified as T3, those with additional nodules in another ipsilateral lobe - as T4. There were no changes in N category. In the M category, M1 was subclassified into M1a (contralateral lung nodules and pleural dissemination) and M1b (distant metastasis). Large T2 tumors (T2bN0M0) were upstaged from IB to IIA, small T2 tumors (T2aN1M0) were downstaged from the IIB to IIA and T4N0-N1M0 - from IIIB to IIIA. The TNM classification was also recommended for small cell lung cancer instead of previously used categories of limited and extensive disease.

  20. MEK inhibitors block growth of lung tumours with mutations in ataxia–telangiectasia mutated

    PubMed Central

    Smida, Michal; Fece de la Cruz, Ferran; Kerzendorfer, Claudia; Uras, Iris Z.; Mair, Barbara; Mazouzi, Abdelghani; Suchankova, Tereza; Konopka, Tomasz; Katz, Amanda M.; Paz, Keren; Nagy-Bojarszky, Katalin; Muellner, Markus K.; Bago-Horvath, Zsuzsanna; Haura, Eric B.; Loizou, Joanna I.; Nijman, Sebastian M. B.

    2016-01-01

    Lung cancer is the leading cause of cancer deaths, and effective treatments are urgently needed. Loss-of-function mutations in the DNA damage response kinase ATM are common in lung adenocarcinoma but directly targeting these with drugs remains challenging. Here we report that ATM loss-of-function is synthetic lethal with drugs inhibiting the central growth factor kinases MEK1/2, including the FDA-approved drug trametinib. Lung cancer cells resistant to MEK inhibition become highly sensitive upon loss of ATM both in vitro and in vivo. Mechanistically, ATM mediates crosstalk between the prosurvival MEK/ERK and AKT/mTOR pathways. ATM loss also enhances the sensitivity of KRAS- or BRAF-mutant lung cancer cells to MEK inhibition. Thus, ATM mutational status in lung cancer is a mechanistic biomarker for MEK inhibitor response, which may improve patient stratification and extend the applicability of these drugs beyond RAS and BRAF mutant tumours. PMID:27922010

  1. Use of the epidermal growth factor receptor inhibitors gefitinib, erlotinib, afatinib, dacomitinib, and icotinib in the treatment of non-small-cell lung cancer: a systematic review

    PubMed Central

    Ellis, P.M.; Coakley, N.; Feld, R.; Kuruvilla, S.; Ung, Y.C.

    2015-01-01

    Introduction This systematic review addresses the use of epidermal growth factor receptor (egfr) inhibitors in three populations of advanced non-small-cell lung cancer (nsclc) patients—unselected, selected, and molecularly selected—in three treatment settings: first line, second line, and maintenance. Methods Ninety-six randomized controlled trials found using the medline and embase databases form the basis of this review. Results In the first-line setting, data about the efficacy of egfr tyrosine kinase inhibitors (tkis) compared with platinum-based chemotherapy are inconsistent. Results from studies that selected patients based on clinical characteristics are also mixed. There is high-quality evidence that an egfr tki is preferred over a platinum doublet as initial therapy for patients with an activating mutation of the EGFR gene. The egfr tkis are associated with a higher likelihood of response, longer progression-free survival, and improved quality of life. Multiple trials of second-line therapy have compared an egfr tki with chemotherapy. Meta-analysis of those data demonstrates similar progression-free and overall survival. There is consequently no preferred sequence for second-line egfr tki or second-line chemotherapy. The egfr tkis have also been evaluated as switch-maintenance therapy. No molecular marker could identify patients in whom a survival benefit was not observed; however, the magnitude of the benefit was modest. Conclusions Determination of EGFR mutation status is essential to making appropriate treatment decisions in patients with nsclc. Patients who are EGFR mutation–positive should be treated with an egfr tki as first-line therapy. An egfr tki is still appropriate therapy in patients who are EGFR wild-type, but the selected agent should be administered as second- or third-line therapy. PMID:26089730

  2. MicroRNA-107 inhibits tumor growth and metastasis by targeting the BDNF-mediated PI3K/AKT pathway in human non-small lung cancer.

    PubMed

    Xia, Huan; Li, Yang; Lv, Xiaohong

    2016-10-01

    Abnormal expression of microRNA-107 (miR-107) was found in non-small cell lung cancer (NSCLC). However, little is known about its role and molecular mechanism in NSCLC progression and metastasis. Therefore, the aims of this study were to clarify the potential role of miR-107 and molecular mechanism in NSCLC progression and metastasis. Quantitative real-time polymerase chain reaction assay showed that miR-107 expression levels were significantly decreased in NSCLC tissue and cell lines. Low miR-107 levels in tumor tissue correlated with advanced TNM stage and lymph node metastasis. Function assays showed that overexpression of miR-107 suppressed cell proliferation, migration and invasion in A549 cells in vitro, and inhibited NSCLC tumor growth in vivo. Further mechanism assays suggested the brain-derived neurotrophic factor (BDNF) was identified as a target gene of miR-107 in NSCLC cells. In addition, BDNF expression was upregulated, and inversely correlated with miR-107 in NSCLC tissues. Enforced overexpression of BDNF effectively reversed the tumor suppressive functions of miR-107 on NSCLC proliferation, migration and invasion. miR-107 overexpression or downregulation of BDNF was able to inhibit activation of PI3K/AKT signaling pathway. Taken together, our findings present the first evidence that miR-107 could suppress NSCLC metastasis by targeting BDNF and indirectly regulating PI3K/AKT signaling pathway, which might lead to a potential therapeutic strategy focusing on miR-107 and BDNF for human NSCLC.

  3. Elevated serum levels of vascular endothelial growth factor predict a poor prognosis of platinum-based chemotherapy in non-small cell lung cancer

    PubMed Central

    Zang, Jialan; Hu, Yong; Xu, Xiaoyue; Ni, Jie; Yan, Dali; Liu, Siwen; He, Jieyu; Xue, Jing; Wu, Jianzhong; Feng, Jifeng

    2017-01-01

    Aim This study was designed to investigate the predictive and prognostic values of serum vascular endothelial growth factor (VEGF) level in non-small cell lung cancer (NSCLC) patients treated with platinum-based chemotherapy. Methods Patients’ peripheral blood samples were collected prior to chemotherapy and after 1 week of the third cycle of combination chemotherapy. Serum VEGF levels were evaluated through Luminex multiplex technique. Between September 2011 and August 2015, a total of 135 consecutive advanced or recurrent histologically verified NSCLC patients were enrolled in the study. Moreover, all the patients received platinum-based combination chemotherapy as a first-line treatment. Results No significant associations were found between pretreatment serum VEGF levels and clinical characteristics, such as sex (P=0.0975), age (P=0.2522), stage (P=0.1407), lymph node metastasis (P=0.6409), tumor location (P=0.3520), differentiated degree (P=0.5608), pathological (histological) type (P=0.4885), and response to treatment (P=0.9859). The VEGF load per platelet (VEGFPLT) levels were not correlated with sex, age, primary tumor site, and pathological type in NSCLC patients (all P>0.05). The median survival time of progression-free survival (PFS) was 6.407 and 5.29 months in the low and high groups, respectively, when using 280 pg/mL VEGF level as the cutoff point (P=0.024). Conclusion In conclusion, the serum VEGF levels were found to be a poor prognostic biomarker for the efficacy of platinum-based chemotherapy in terms of PFS, but it was not shown to be a suitable predictive marker for clinical response to platinum-based chemotherapy. PMID:28176920

  4. The role of epithelial to mesenchymal transition in resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer

    PubMed Central

    Jakobsen, Kristine Raaby; Demuth, Christina; Sorensen, Boe Sandahl

    2016-01-01

    Inhibition of the epidermal growth factor receptor (EGFR) is an important strategy when treating non-small cell lung cancer (NSCLC) patients. However, intrinsic resistance or development of resistance during the course of treatment constitutes a major challenge. The knowledge on EGFR-directed tyrosine kinase inhibitors (TKIs) and their biological effect keeps increasing. Within the group of patients with EGFR mutations some benefit to a much higher degree than others, and for patients lacking EGFR mutations a subset experience an effect. Up to 70% of patients with EGFR mutations and 10–20% of patients without EGFR mutations initially respond to the EGFR-TKI erlotinib, but there is a severe absence of good prognostic markers. Despite initial effect, all patients acquire resistance to EGFR-TKIs. Multiple mechanisms have implications in resistance development, but much is still to be explored. Epithelial to mesenchymal transition (EMT) is a transcriptionally regulated phenotypic shift rendering cells more invasive and migratory. Within the EMT process lays a need for external or internal stimuli to give rise to changes in central signaling pathways. Expression of mesenchymal markers correlates to a bad prognosis and an inferior response to EGFR-TKIs in NSCLC due to the contribution to a resistant phenotype. A deeper understanding of the role of EMT in NSCLC and especially in EGFR-TKI resistance-development constitute one opportunity to improve the benefit of TKI treatment for the individual patient. Many scientific studies have linked the EMT process to EGFR-TKI resistance in NSCLC and our aim is to review the role of EMT in both intrinsic and acquired resistance to EGFR-TKIs. PMID:27186512

  5. The impact of metformin and salinomycin on transforming growth factor β-induced epithelial-to-mesenchymal transition in non-small cell lung cancer cell lines.

    PubMed

    Koeck, Stefan; Amann, Arno; Huber, Julia M; Gamerith, Gabriele; Hilbe, Wolfgang; Zwierzina, Heinz

    2016-04-01

    The epithelial-to-mesenchymal transition (EMT) is highly involved in the development of metastases. EMT transforms epithelial carcinoma cells into mesenchymal-like cells, characterized by increased cell migration and invasiveness. Transforming growth factor β (TGFβ) appears to be crucial in this process. Metformin and salinomycin have demonstrated an EMT inhibitory effect. The current experiments indicate that these substances specifically inhibit TGFβ-induced EMT in non-small cell lung cancer (NSCLC) cell lines. The NSCLC cell lines A549 and HCC4006 were stimulated with TGFβ for 48 h to induce EMT. Metformin or salinomycin was added simultaneously with TGFβ to inhibit TGFβ-induced EMT. Western blot analyses of E-cadherin and vimentin were performed to detect changes in EMT marker expression, and a wound healing assay was conducted to determine the potential effects on cell migration. The effects of the two drugs on cell viability were also investigated using MTS tetrazolium dye assays. The results revealed that cells undergoing EMT by application of TGFβ exhibited a downregulation of E-cadherin and an upregulation of vimentin protein expression on western blot analyses, and an increased capacity for cell migration. Simultaneous application of TGFβ and metformin specifically inhibited EMT and increased E-cadherin expression. At the higher dose tested, salinomycin also inhibited EMT, despite an increase in vimentin expression in the two cell lines. Furthermore, metformin and salinomycin, at the two concentrations tested, inhibited cell migration. These findings demonstrate that metformin and salinomycin are able to block EMT and inhibit EMT-induced cell migration. Thus, these two substances are novel EMT inhibiting drugs that have the potential to specifically control EMT and metastatic spread in NSCLC.

  6. Correlation between epidermal growth factor receptor tyrosine kinase inhibitor efficacy and circulating tumor cell levels in patients with advanced non-small cell lung cancer

    PubMed Central

    He, Wenjie; Li, Wenhui; Jiang, Bo; Chang, Li; Jin, Congguo; Tu, Changlin; Li, Yunfen

    2016-01-01

    Objective The aim of this study was to investigate the correlation between the efficacy of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) and circulating tumor cell (CTC) levels in patients with advanced non-small cell lung cancer (NSCLC). The efficacy of EGFR-TKIs in reducing CTC counts in patients with advanced NSCLC was studied. Patients and methods A total of 66 patients with advanced NSCLC were enrolled and divided into two groups (those with high CTC counts and those with low CTC counts) based on the patients’ median CTC counts. All the patients were treated with an EGFR-TKI, and the treatment efficacy and prognoses were compared. Results The treatment efficacies were 53.3% (16/30) and 27.8% (10/36) for the low CTC group and high CTC group, respectively, and this difference was statistically significant (P<0.05). The median overall survival was 22.8 months (95% confidence interval [CI]: 18.9–26.8 months) for the low CTC group and 18.3 months (95% CI: 2.9–8.2 months) for the high CTC group. The median progression-free survival was 11.5 months (95% CI: 8.1–15 months) and 5.6 months (95% CI: 2.9–8.2 months) for the low and high CTC groups, respectively, and the difference was statistically significant (P<0.05). Conclusion The CTC count can be used as an index for predicting the EGFR-TKI effect on patients with advanced NSCLC. Efficacy and prognosis of EGFR-TKI treatment and CTC count were considered important, and the CTC count could be used to predict the efficacy of EGFR-TKI treatment and prognosis of advanced NSCLC. The change in CTC expression levels can be used as an index for evaluating the prognosis of patients with advanced NSCLC. PMID:28003764

  7. Basic Fibroblast Growth Factor-2/beta3 Integrin Expression Profile: Signature of Local Progression After Chemoradiotherapy for Patients With Locally Advanced Non-Small-Cell Lung Cancer

    SciTech Connect

    Massabeau, Carole; Rouquette, Isabelle; Lauwers-Cances, Valerie; Mazieres, Julien; Bachaud, Jean-Marc; Armand, Jean-Pierre; Delisle, Marie-Bernadette; Favre, Gilles; Toulas, Christine; Cohen-Jonathan-Moyal, Elizabeth

    2009-11-01

    Purpose: No biologic signature of chemoradiotherapy sensitivity has been reported for patients with locally advanced non-small-cell lung cancer (NSCLC). We have previously demonstrated that basic fibroblast growth factor (FGF-2) and alphavbeta3 integrin pathways control tumor radioresistance. We investigated whether the expression of the proteins involved in these pathways might be associated with the response to treatment and, therefore, the clinical outcome. Methods and Materials: FGF-2, beta3 integrin, angiopoietin-2, and syndecan-1 expression was studied using immunohistochemistry performed on biopsies obtained, before any treatment, from 65 patients exclusively treated with chemoradiotherapy for locally advanced NSCLC. The response to treatment was evaluated according to the Response Evaluation Criteria in Solid Tumors criteria using computed tomography at least 6 weeks after the end of the chemoradiotherapy. Local progression-free survival, metastasis-free survival, and disease-free survival were studied using the log-rank test and Cox proportional hazard analysis. Results: Among this NSCLC biopsy population, 43.7% overexpressed beta3 integrin (beta3{sup +}), 43% FGF-2 (FGF-2{sup +}), 41.5% syndecan-1, and 59.4% angiopoietin-2. Our results showed a strong association between FGF-2 and beta3 integrin expression (p = .001). The adjusted hazard ratio of local recurrence for FGF-2{sup +}/beta3{sup +} tumors compared with FGF-2{sup -}/beta3{sup -} tumors was 6.1 (95% confidence interval, 2.6-14.6, p = .005). However, the risk of local recurrence was not increased when tumors overexpressed beta3 integrin or FGF-2 alone. Moreover, the co-expression of these two proteins was marginally associated with the response to chemoradiotherapy and metastasis-free survival. Conclusion: The results of this study have identified the combined profile FGF-2/beta3 integrin expression as a signature of local control in patients treated with chemoradiotherapy for locally advanced

  8. Molecular determinants of drug-specific sensitivity for epidermal growth factor receptor (EGFR) exon 19 and 20 mutants in non-small cell lung cancer.

    PubMed

    Tsigelny, Igor F; Wheler, Jennifer J; Greenberg, Jerry P; Kouznetsova, Valentina L; Stewart, David J; Bazhenova, Lyudmila; Kurzrock, Razelle

    2015-03-20

    We hypothesized that aberrations activating epidermal growth factor receptor (EGFR) via dimerization would be more sensitive to anti-dimerization agents (e.g., cetuximab). EGFR exon 19 abnormalities (L747_A750del; deletes amino acids LREA) respond to reversible EGFR kinase inhibitors (TKIs). Exon 20 in-frame insertions and/or duplications (codons 767 to 774) and T790M mutations are clinically resistant to reversible/some irreversible TKIs. Their impact on protein function/therapeutic actionability are not fully elucidated.In our study, the index patient with non-small cell lung cancer (NSCLC) harbored EGFR D770_P772del_insKG (exon 20). A twenty patient trial (NSCLC cohort) (cetuximab-based regimen) included two participants with EGFR TKI-resistant mutations ((i) exon 20 D770>GY; and (ii) exon 19 LREA plus exon 20 T790M mutations). Structural modeling predicted that EGFR exon 20 anomalies (D770_P772del_insKG and D770>GY), but not T790M mutations, stabilize the active dimer configuration by increasing the interaction between the kinase domains, hence sensitizing to an agent preventing dimerization. Consistent with predictions, the two patients harboring D770_P772del_insKG and D770>GY, respectively, responded to an EGFR antibody (cetuximab)-based regimen; the T790M-bearing patient showed no response to cetuximab combined with erlotinib. In silico modeling merits investigation of its ability to optimize therapeutic selection based on structural/functional implications of different aberrations within the same gene.

  9. Polo-like kinase 1 inhibition diminishes acquired resistance to epidermal growth factor receptor inhibition in non-small cell lung cancer with T790M mutations

    PubMed Central

    Wang, Liguang; Nilsson, Monique; Goonatilake, Ruchitha; Tong, Pan; Li, Lerong; Giri, Uma; Villalobos, Pamela; Mino, Barbara; Rodriguez-Canales, Jaime; Wistuba, Ignacio; Wang, Jing; Heymach, John V.; Johnson, Faye M.

    2016-01-01

    Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are effective against non-small cell lung cancer (NSCLC) with activating EGFR mutations, but resistance is inevitable. Mechanisms of acquired resistance include T790M mutations and epithelial–mesenchymal transition (EMT). One potential strategy for overcoming this resistance is the inhibition of polo-like kinase 1 (PLK1) based on our previous studies showing that mesenchymal NSCLC cell lines are more sensitive to PLK1 inhibition than epithelial cell lines. To determine the extent to which PLK1 inhibition overcomes EGFR TKI resistance we measured the effects of the PLK1 inhibitor volasertib alone and in combination with the EGFR inhibitor erlotinib in vitro and in vivo in EGFR mutant NSCLC cell lines with acquired resistance to erlotinib. Two erlotinib-resistant cell lines that underwent EMT had higher sensitivity to volasertib, which caused G2/M arrest and apoptosis, than their parental cells. In all NSCLC cell lines with T790M mutations, volasertib markedly reduced erlotinib resistance. All erlotinib-resistant NSCLC cell lines with T790M mutations had higher sensitivity to erlotinib plus volasertib than to erlotinib alone, and the combination treatment caused G2/M arrest and apoptosis. Compared with either agent alone, the combination treatment also caused significantly more DNA damage and greater reductions in tumor size. Our results suggest that PLK1 inhibition is clinically effective against NSCLC that becomes resistant to EGFR inhibition through EMT or the acquisition of a T790M mutation. These results uncover new functions of PLK1 inhibition in the treatment of NSCLC with acquired resistance to EGFR TKIs. PMID:27384992

  10. ZEB1 Mediates Acquired Resistance to the Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors in Non-Small Cell Lung Cancer

    PubMed Central

    Yoshida, Takeshi; Song, Lanxi; Bai, Yun; Kinose, Fumi; Li, Jiannong; Ohaegbulam, Kim C.; Muñoz-Antonia, Teresita; Qu, Xiaotao; Eschrich, Steven; Uramoto, Hidetaka; Tanaka, Fumihiro; Nasarre, Patrick; Gemmill, Robert M.; Roche, Joëlle; Drabkin, Harry A.; Haura, Eric B.

    2016-01-01

    Epithelial-mesenchymal transition (EMT) is one mechanism of acquired resistance to inhibitors of the epidermal growth factor receptor-tyrosine kinases (EGFR-TKIs) in non-small cell lung cancer (NSCLC). The precise mechanisms of EMT-related acquired resistance to EGFR-TKIs in NSCLC remain unclear. We generated erlotinib-resistant HCC4006 cells (HCC4006ER) by chronic exposure of EGFR-mutant HCC4006 cells to increasing concentrations of erlotinib. HCC4006ER cells acquired an EMT phenotype and activation of the TGF-β/SMAD pathway, while lacking both T790M secondary EGFR mutation and MET gene amplification. We employed gene expression microarrays in HCC4006 and HCC4006ER cells to better understand the mechanism of acquired EGFR-TKI resistance with EMT. At the mRNA level, ZEB1 (TCF8), a known regulator of EMT, was >20-fold higher in HCC4006ER cells than in HCC4006 cells, and increased ZEB1 protein level was also detected. Furthermore, numerous ZEB1 responsive genes, such as CDH1 (E-cadherin), ST14, and vimentin, were coordinately regulated along with increased ZEB1 in HCC4006ER cells. We also identified ZEB1 overexpression and an EMT phenotype in several NSCLC cells and human NSCLC samples with acquired EGFR-TKI resistance. Short-interfering RNA against ZEB1 reversed the EMT phenotype and, importantly, restored erlotinib sensitivity in HCC4006ER cells. The level of micro-RNA-200c, which can negatively regulate ZEB1, was significantly reduced in HCC4006ER cells. Our results suggest that increased ZEB1 can drive EMT-related acquired resistance to EGFR-TKIs in NSCLC. Attempts should be made to explore targeting ZEB1 to resensitize TKI-resistant tumors. PMID:26789630

  11. Racial and Ethnic Differences in the Epidemiology of Lung Cancer and the Lung Cancer Genome

    PubMed Central

    Schabath, Matthew B.; Cress, W. Douglas; Muñoz-Antonia, Teresita

    2017-01-01

    Background Globally and in the United States, lung cancer has been the most common cancer for the past several decades. In addition to the well-established geographical- and sex-specific differences in lung cancer incidence, mortality and survival, there is also growing evidence for racial and ethnic differences. Methods Based on available published data, we present a summary of the current knowledge and substantive findings related to racial and ethnic differences in lung cancer. Results Although this report is not a systematic review, we summarized the current knowledge and substantive findings related to racial and ethnic differences in lung cancer with a particular focus on lung cancer statistics(incidence, mortality, and survival), cigarette smoking, prevention and early detection, and the lung cancer genome. Finally, we summarize some the systems-level and provider-related issues that likely contribute to racial and ethnic-specific health disparities and provide some suggestions for future strategies that may reduce the disproportionate burden of lung cancer. Conclusions Although lung carcinogenesis is a multifactorial process driven by exogenous exposures (e.g., cigarette smoking), inherited genetic variations, and an accumulation of somatic genetic events, this multifactorial process appears to have racial and ethnic differences which in turn impacts the observed epidemiologic differences in incidence, mortality, and survival. PMID:27842323

  12. Mortality due to lung cancer in Mexico.

    PubMed

    Ruíz-Godoy, L; Rizo Rios, P; Sánchez Cervantes, F; Osornio-Vargas, A; García-Cuellar, C; Meneses García, A

    2007-11-01

    The highest mortality due to cancer worldwide for both genders corresponds to lung cancer (1,179,000 deaths). In Mexico, the crude mortality rate due to lung cancer was of 5.01 per 10(5) inhabitants in 1979. The most important risk factor is smoking. The present study was aimed at analyzing the mortality due to lung cancer in Mexico, assessing data from each of the states constituting the Mexican Republic during the 1998-2004 period. Data were obtained from the National Institute of Statistics, Geography and Informatics (INEGI, for its initials in Spanish) corresponding to deaths due to lung cancer (1998-2004). We estimated the mean annual mortality rate (MAMR) for each of the 32 states of Mexico. We used the "World Population Standard". The MAMR was standardized according to age (ARS) direct method, and the standard error was determined by Poisson's approximation at a 95% confidence interval. To know the excess risk due to mortality, we calculated the standardized mortality ratios (SMRs) of ARS for each federal state, using the national rate as reference. In this period, 397,400 deaths due to malignant neoplasms were recorded, corresponding 45,578 (11.5%) to lung cancer; for men, 31,025 (68.1%) with MAMR of 8.9 and the respective ARS of 13.2 both x10(5) inhabitants. For women, results were 4553 (31.9%) deaths with MAMR of 4.1 and ARS of 5.4 both x10(5) inhabitants. The highest mortality rates due to lung cancer in both genders were observed in the north of Mexico, whereas for women this was observed in the central states. Although smoking is the main risk for lung cancer, there are other factors such as environmental pollution or exposure to toxicants that could be associated to this cancer. The years potentially lost due to lung cancer were 258,550 for men and 133,315 for women, with a total of 391,865 according to histopathology registry neoplasm malignant RHNM (1985-1995). Studies focused on the characterization and measurement of polluting agents would be a

  13. Matrix Metalloproteinase Mmp-1a Is Dispensable for Normal Growth and Fertility in Mice and Promotes Lung Cancer Progression by Modulating Inflammatory Responses*

    PubMed Central

    Fanjul-Fernández, Miriam; Folgueras, Alicia R.; Fueyo, Antonio; Balbín, Milagros; Suárez, María F.; Fernández-García, M. Soledad; Shapiro, Steven D.; Freije, José M. P.; López-Otín, Carlos

    2013-01-01

    Human MMP-1 is a matrix metalloproteinase repeatedly associated with many pathological conditions, including cancer. Thus, MMP1 overexpression is a poor prognosis marker in a variety of advanced cancers, including colorectal, breast, and lung carcinomas. Moreover, MMP-1 plays a key role in the metastatic behavior of melanoma, breast, and prostate cancer cells. However, functional and mechanistic studies on the relevance of MMP-1 in cancer have been hampered by the absence of an in vivo model. In this work, we have generated mice deficient in Mmp1a, the murine ortholog of human MMP1. Mmp1a−/− mice are viable and fertile and do not exhibit obvious abnormalities, which has facilitated studies of cancer susceptibility. These studies have shown a decreased susceptibility to develop lung carcinomas induced by chemical carcinogens in Mmp1a−/− mice. Histopathological analysis indicated that tumors generated in Mmp1a−/− mice are smaller than those of wild-type mice, consistently with the idea that the absence of Mmp-1a hampers tumor progression. Proteomic analysis revealed decreased levels of chitinase-3-like 3 and accumulation of the receptor for advanced glycation end-products and its ligand S100A8 in lung samples from Mmp1a−/− mice compared with those from wild-type. These findings suggest that Mmp-1a could play a role in tumor progression by modulating the polarization of a Th1/Th2 inflammatory response to chemical carcinogens. On the basis of these results, we propose that Mmp1a knock-out mice provide an excellent in vivo model for the functional analysis of human MMP-1 in both physiological and pathological conditions. PMID:23548910

  14. Treatment options for small cell lung cancer.

    PubMed

    Wolf, Todd; Gillenwater, Heidi H

    2004-07-01

    Lung cancer remains the leading cause of cancer-related death in the United States. Small cell lung cancer (SCLC) comprises 15% to 25% of all lung cancers. The leading cause of lung cancer remains smoking, and rates of smoking continue to rise in women, whereas rates in other subgroups have slowed. In this article we review recent advances in the treatment of limited-stage as well as extensive-stage small cell lung cancer. In limited-stage disease, the best survival results are observed when patients are treated with twice-daily thoracic radiotherapy given concurrently with chemotherapy. Patients who have been successful in smoking cessation during therapy for limited-stage disease may have a survival benefit over those who are unable to quit smoking during treatment. In extensive-stage disease, the most significant trial is one comparing irinotecan plus cisplatin and etoposide plus cisplatin, showing a survival advantage for the irinotecan arm. This trial may change the standard of care for patients with extensive-stage disease. A similar ongoing trial in the United States is attempting to confirm these results.

  15. Paraneoplastic syndromes associated with lung cancer

    PubMed Central

    Kanaji, Nobuhiro; Watanabe, Naoki; Kita, Nobuyuki; Bandoh, Shuji; Tadokoro, Akira; Ishii, Tomoya; Dobashi, Hiroaki; Matsunaga, Takuya

    2014-01-01

    Paraneoplastic syndromes are signs or symptoms that occur as a result of organ or tissue damage at locations remote from the site of the primary tumor or metastases. Paraneoplastic syndromes associated with lung cancer can impair various organ functions and include neurologic, endocrine, dermatologic, rheumatologic, hematologic, and ophthalmological syndromes, as well as glomerulopathy and coagulopathy (Trousseau’s syndrome). The histological type of lung cancer is generally dependent on the associated syndrome, the two most common of which are humoral hypercalcemia of malignancy in squamous cell carcinoma and the syndrome of inappropriate antidiuretic hormone secretion in small cell lung cancer. The symptoms often precede the diagnosis of the associated lung cancer, especially when the symptoms are neurologic or dermatologic. The proposed mechanisms of paraneoplastic processes include the aberrant release of humoral mediators, such as hormones and hormone-like peptides, cytokines, and antibodies. Treating the underlying cancer is generally the most effective therapy for paraneoplastic syndromes, and treatment soon after symptom onset appears to offer the best potential for symptom improvement. In this article, we review the diagnosis, potential mechanisms, and treatments of a wide variety of paraneoplastic syndromes associated with lung cancer. PMID:25114839

  16. Risk of lung cancer in Parkinson's disease

    PubMed Central

    Xie, Xin; Luo, Xiaoguang; Xie, Mingliang; Liu, Yang; Wu, Ting

    2016-01-01

    Recently, growing evidence has revealed the significant association between Parkinson's disease (PD) and cancer. However, controversy still exists concerning the association between PD and lung cancer. A comprehensive article search for relevant studies published was performed using the following online databases: PubMed, Web of Science and Embase up to August 31, 2016. The pooled risk ratio (RR) and their 95 % confidence intervals (CI) were calculated using the method of inverse variance with the random-effects model. Fifteen studies comprising 348,780 PD patients were included in this study. The pooled result indicated that patients with PD were significantly associated with a decreased risk of lung cancer (RR: 0.53, 95% CI: 0.41−0.70, P < 0.001). In addition, subgroup analyses performed in Western population also confirmed the significant inverse relationship between PD and risk of lung cancer (RR: 0.48, 95% CI: 0.39−0.60, P < 0.001). In the subgroup analysis, a reduced risk of lung cancer in PD patients from Western population was consistent regardless of study design, gender, or study quality. In conclusion, PD patients were significantly associated with a reduced risk of lung cancer in Western population. The relationship between them in Asian population needs to be confirmed by future studies. PMID:27801674

  17. Retinoids in lung cancer chemoprevention and treatment.

    PubMed

    Toma, S; Raffo, P; Isnardi, L; Palumbo, R

    1999-01-01

    In this review, we aim to synthesize the emerging picture of retinoids in lung cancer through a summary of ongoing investigations in biology, chemoprevention and therapy settings, in an attempt to clarify the possible role of these agents in such a disease. Early work in head and neck cancer has evidenced the capability of retinoids to interrupt field carcinogenesis by reversing premalignant lesions and decreasing the incidence of second primary tumors (SPTs). At this time, the completed randomized trials in lung cancer have failed to demonstrate an evident chemopreventive effect of the tested agents on different study end points, although both a marginally significant benefit of retinol palmitate in time-to-development rates for smoke-related SPTs and a potential preventive effect of retinol supplementation against mesothelioma in selected populations of asbestos-exposed workers have been recently reported. Concerning the role of retinoids in lung cancer treatment, a moderate activity of 13-cis-retinoic acid (13cRA) or all-transretinoic acid (ATRA) as single agents has been reported in small series of advanced, mostly pretreated lung cancer patients. More encouraging findings derive from combination studies, in which retinoids, especially ATRA, are added to either alpha-interferon or chemotherapy and radiotherapy. Major recent advances have been made towards the understanding of retinoids mechanisms of action; at this regard, the role of RAR-beta basal or treatment-induced levels seems to be of particular interest as intermediate end point and/or independent prognostic factor, besides their known importance in lung carcinogenesis. Future research for chemopreventive and therapeutic programs with retinoids in lung cancer should be focused on the investigation of new generation compounds with a specificity for individual retinoid nuclear receptors. Such selective molecules may have a greater activity against lung cancer, with a more favourable toxicity profile, as

  18. 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

    2016-11-01

    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

  19. 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.

  20. A combinatorial strategy for treating KRAS-mutant lung cancer.

    PubMed

    Manchado, Eusebio; Weissmueller, Susann; Morris, John P; Chen, Chi-Chao; Wullenkord, Ramona; Lujambio, Amaia; de Stanchina, Elisa; Poirier, John T; Gainor, Justin F; Corcoran, Ryan B; Engelman, Jeffrey A; Rudin, Charles M; Rosen, Neal; Lowe, Scott W

    2016-06-30

    Therapeutic targeting of KRAS-mutant lung adenocarcinoma represents a major goal of clinical oncology. KRAS itself has proved difficult to inhibit, and the effectiveness of agents that target key KRAS effectors has been thwarted by activation of compensatory or parallel pathways that limit their efficacy as single agents. Here we take a systematic approach towards identifying combination targets for trametinib, a MEK inhibitor approved by the US Food and Drug Administration, which acts downstream of KRAS to suppress signalling through the mitogen-activated protein kinase (MAPK) cascade. Informed by a short-hairpin RNA screen, we show that trametinib provokes a compensatory response involving the fibroblast growth factor receptor 1 (FGFR1) that leads to signalling rebound and adaptive drug resistance. As a consequence, genetic or pharmacological inhibition of FGFR1 in combination with trametinib enhances tumour cell death in vitro and in vivo. This compensatory response shows distinct specificities: it is dominated by FGFR1 in KRAS-mutant lung and pancreatic cancer cells, but is not activated or involves other mechanisms in KRAS wild-type lung and KRAS-mutant colon cancer cells. Importantly, KRAS-mutant lung cancer cells and patients’ tumours treated with trametinib show an increase in FRS2 phosphorylation, a biomarker of FGFR activation; this increase is abolished by FGFR1 inhibition and correlates with sensitivity to trametinib and FGFR inhibitor combinations. These results demonstrate that FGFR1 can mediate adaptive resistance to trametinib and validate a combinatorial approach for treating KRAS-mutant lung cancer.

  1. A combinatorial strategy for treating KRAS mutant lung cancer

    PubMed Central

    Manchado, Eusebio; Weissmueller, Susann; Morris, John P.; Chen, Chi-Chao; Wullenkord, Ramona; Lujambio, Amaia; de Stanchina, Elisa; Poirier, John T.; Gainor, Justin F.; Corcoran, Ryan B.; Engelman, Jeffrey A.; Rudin, Charles M.; Rosen, Neal; Lowe, Scott W.

    2016-01-01

    Therapeutic targeting of KRAS-mutant lung adenocarcinoma represents a major goal of clinical oncology. KRAS itself has proven difficult to inhibit, and the effectiveness of agents that target key KRAS effectors has been thwarted by activation of compensatory or parallel pathways that limit their efficacy as single agents. Here we take a systematic approach towards identifying combination targets for trametinib, an FDA-approved MEK inhibitor that acts downstream of KRAS to suppress signaling through the mitogen-activated protein kinase (MAPK) cascade. Informed by a short-hairpin RNA (shRNA) screen, we show that trametinib provokes a compensatory response involving the fibroblast growth factor receptor 1 (FGFR1) that leads to signaling rebound and adaptive drug resistance. As a consequence, genetic or pharmacologic inhibition of FGFR1 in combination with trametinib enhances tumor cell death in vitro and in vivo. This compensatory response shows distinct specificities – it is dominated by FGFR1 in KRAS mutant lung and pancreatic cancer cells, but is not activated or involves other mechanisms in KRAS wild-type lung and KRAS-mutant colon cancer cells. Importantly, KRAS-mutant lung cancer cells and patient tumors treated with trametinib show an increase in FRS2 phosphorylation, a biomarker of FGFR activation; this increase is abolished by FGFR1 inhibition and correlates with sensitivity to trametinib and FGFR inhibitor combinations. These results demonstrate that FGFR1 can mediate adaptive resistance to trametinib and validate a combinatorial approach for treating KRAS-mutant lung cancer. PMID:27338794

  2. Inhalable Magnetic Nanoparticles for Targeted Hyperthermia in Lung Cancer Therapy

    PubMed Central

    Sadhukha, Tanmoy; Wiedmann, Timothy Scott; Panyam, Jayanth

    2015-01-01

    Lung cancer (specifically, non-small cell lung cancer; NSCLC) is the leading cause of cancer-related deaths in the United States. Poor response rates and survival with current treatments clearly indicate the urgent need for developing an effective means to treat NSCLC. Magnetic hyperthermia is a non-invasive approach for tumor ablation, and is based on heat generation by magnetic materials, such as superparamagnetic iron oxide (SPIO) nanoparticles, when subjected to an alternating magnetic field. However, inadequate delivery of magnetic nanoparticles to tumor cells can result in sub-lethal temperature change and induce resistance while non-targeted delivery of these particles to the healthy tissues can result in toxicity. In our studies, we evaluated the effectiveness of tumor-targeted SPIO nanoparticles for magnetic hyperthermia of lung cancer. EGFR-targeted, inhalable SPIO nanoparticles were synthesized and characterized for targeting lung tumor cells as well as for magnetic hyperthermia-mediated antitumor efficacy in a mouse orthotopic model of NSCLC. Our results show that EGFR targeting enhances tumor retention of SPIO nanoparticles. Further, magnetic hyperthermia treatment using targeted SPIO nanoparticles resulted in significant inhibition of in vivo lung tumor growth. Overall, this work demonstrates the potential for developing an effective anticancer treatment modality for the treatment of NSCLC based on targeted magnetic hyperthermia. PMID:23591395

  3. Molecular understanding of lung cancers-A review

    PubMed Central

    Singh, Chinnappan Ravinder; Kathiresan, Kandasamy

    2014-01-01

    Lung cancer is considered to be the most common cancer in the world. The purpose of this paper is to review scientific evidence, particularly epidemiologic evidence of overall lung cancer burden in the world. And molecular understanding of lung cancer at various levels by dominant and suppressor oncogenes. PMID:25183110

  4. 28 CFR 79.64 - Proof of primary lung cancer.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 28 Judicial Administration 2 2011-07-01 2011-07-01 false Proof of primary lung cancer. 79.64... cancer. (a) In determining whether a claimant developed primary lung cancer following pertinent... claimant. A conclusion that a claimant developed primary lung cancer must be supported by...

  5. 28 CFR 79.45 - Proof of primary lung cancer.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 28 Judicial Administration 2 2011-07-01 2011-07-01 false Proof of primary lung cancer. 79.45... cancer. (a) In determining whether a claimant developed primary lung cancer following pertinent... conclusion that a claimant developed primary lung cancer must be supported by medical documentation. To...

  6. 28 CFR 79.54 - Proof of primary lung cancer.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 28 Judicial Administration 2 2014-07-01 2014-07-01 false Proof of primary lung cancer. 79.54... cancer. (a) In determining whether a claimant developed primary lung cancer following pertinent... conclusion that a claimant developed primary lung cancer must be supported by medical documentation. To...

  7. 28 CFR 79.54 - Proof of primary lung cancer.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 28 Judicial Administration 2 2012-07-01 2012-07-01 false Proof of primary lung cancer. 79.54... cancer. (a) In determining whether a claimant developed primary lung cancer following pertinent... conclusion that a claimant developed primary lung cancer must be supported by medical documentation. To...

  8. 28 CFR 79.45 - Proof of primary lung cancer.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 28 Judicial Administration 2 2012-07-01 2012-07-01 false Proof of primary lung cancer. 79.45... cancer. (a) In determining whether a claimant developed primary lung cancer following pertinent... conclusion that a claimant developed primary lung cancer must be supported by medical documentation. To...

  9. 28 CFR 79.45 - Proof of primary lung cancer.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 28 Judicial Administration 2 2010-07-01 2010-07-01 false Proof of primary lung cancer. 79.45... cancer. (a) In determining whether a claimant developed primary lung cancer following pertinent... conclusion that a claimant developed primary lung cancer must be supported by medical documentation. To...

  10. 28 CFR 79.54 - Proof of primary lung cancer.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 28 Judicial Administration 2 2013-07-01 2013-07-01 false Proof of primary lung cancer. 79.54... cancer. (a) In determining whether a claimant developed primary lung cancer following pertinent... conclusion that a claimant developed primary lung cancer must be supported by medical documentation. To...

  11. 28 CFR 79.45 - Proof of primary lung cancer.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 28 Judicial Administration 2 2014-07-01 2014-07-01 false Proof of primary lung cancer. 79.45... cancer. (a) In determining whether a claimant developed primary lung cancer following pertinent... conclusion that a claimant developed primary lung cancer must be supported by medical documentation. To...

  12. 28 CFR 79.64 - Proof of primary lung cancer.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 28 Judicial Administration 2 2010-07-01 2010-07-01 false Proof of primary lung cancer. 79.64... cancer. (a) In determining whether a claimant developed primary lung cancer following pertinent... claimant. A conclusion that a claimant developed primary lung cancer must be supported by...

  13. 28 CFR 79.54 - Proof of primary lung cancer.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 28 Judicial Administration 2 2011-07-01 2011-07-01 false Proof of primary lung cancer. 79.54... cancer. (a) In determining whether a claimant developed primary lung cancer following pertinent... conclusion that a claimant developed primary lung cancer must be supported by medical documentation. To...

  14. 28 CFR 79.54 - Proof of primary lung cancer.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 28 Judicial Administration 2 2010-07-01 2010-07-01 false Proof of primary lung cancer. 79.54... cancer. (a) In determining whether a claimant developed primary lung cancer following pertinent... conclusion that a claimant developed primary lung cancer must be supported by medical documentation. To...

  15. 28 CFR 79.64 - Proof of primary lung cancer.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 28 Judicial Administration 2 2014-07-01 2014-07-01 false Proof of primary lung cancer. 79.64... cancer. (a) In determining whether a claimant developed primary lung cancer following pertinent... claimant. A conclusion that a claimant developed primary lung cancer must be supported by...

  16. 28 CFR 79.45 - Proof of primary lung cancer.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 28 Judicial Administration 2 2013-07-01 2013-07-01 false Proof of primary lung cancer. 79.45... cancer. (a) In determining whether a claimant developed primary lung cancer following pertinent... conclusion that a claimant developed primary lung cancer must be supported by medical documentation. To...

  17. 28 CFR 79.64 - Proof of primary lung cancer.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 28 Judicial Administration 2 2013-07-01 2013-07-01 false Proof of primary lung cancer. 79.64... cancer. (a) In determining whether a claimant developed primary lung cancer following pertinent... claimant. A conclusion that a claimant developed primary lung cancer must be supported by...

  18. 28 CFR 79.64 - Proof of primary lung cancer.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 28 Judicial Administration 2 2012-07-01 2012-07-01 false Proof of primary lung cancer. 79.64... cancer. (a) In determining whether a claimant developed primary lung cancer following pertinent... claimant. A conclusion that a claimant developed primary lung cancer must be supported by...

  19. Nexus of signaling and endocytosis in oncogenesis driven by non-small cell lung cancer-associated epidermal growth factor receptor mutants

    PubMed Central

    Chung, Byung Min; Tom, Eric; Zutshi, Neha; Bielecki, Timothy Alan; Band, Vimla; Band, Hamid

    2014-01-01

    Epidermal growth factor receptor (EGFR) controls a wide range of cellular processes, and aberrant EGFR signaling as a result of receptor overexpression and/or mutation occurs in many types of cancer. Tumor cells in non-small cell lung cancer (NSCLC) patients that harbor EGFR kinase domain mutations exhibit oncogene addiction to mutant EGFR, which confers high sensitivity to tyrosine kinase inhibitors (TKIs). As patients invariably develop resistance to TKIs, it is important to delineate the cell biological basis of mutant EGFR-induced cellular transformation since components of these pathways can serve as alternate therapeutic targets to preempt or overcome resistance. NSCLC-associated EGFR mutants are constitutively-active and induce ligand-independent transformation in nonmalignant cell lines. Emerging data suggest that a number of factors are critical for the mutant EGFR-dependent tumorigenicity, and bypassing the effects of TKIs on these pathways promotes drug resistance. For example, activation of downstream pathways such as Akt, Erk, STAT3 and Src is critical for mutant EGFR-mediated biological processes. It is now well-established that the potency and spatiotemporal features of cellular signaling by receptor tyrosine kinases such as EGFR, as well as the specific pathways activated, is determined by the nature of endocytic traffic pathways through which the active receptors traverse. Recent evidence indicates that NSCLC-associated mutant EGFRs exhibit altered endocytic trafficking and they exhibit reduced Cbl ubiquitin ligase-mediated lysosomal downregulation. More recent work has shown that mutant EGFRs undergo ligand-independent traffic into the endocytic recycling compartment, a behavior that plays a key role in Src pathway activation and oncogenesis. These studies are beginning to delineate the close nexus between signaling and endocytic traffic of EGFR mutants as a key driver of oncogenic processes. Therefore, in this review, we will discuss the links

  20. Genetic variations in the transforming growth factor-beta pathway as predictors of survival in advanced non-small cell lung cancer

    PubMed Central

    Stewart, David J.; Spitz, Margaret R.; Hildebrandt, Michelle A.T.; Lu, Charles; Lin, Jie; Gu, Jian; Huang, Maosheng; Lippman, Scott M.; Wu, Xifeng

    2011-01-01

    The magnitude of benefit is variable for advanced non-small cell lung cancer (NSCLC) patients receiving platinum-based chemotherapy. The purpose of this study is to determine whether genetic variations in the transforming growth factor-beta (TGF-β) pathway are associated with clinical outcomes in NSCLC patients receiving first-line platinum-based chemotherapy. Five hundred and ninety-eight advanced-stage NSCLC patients who received first-line platinum-based chemotherapy with or without radiotherapy were recruited at the MD Anderson Cancer Center between 1995 and 2007. DNA from blood was genotyped for 227 single nucleotide polymorphisms (SNPs) in 23 TGF-β pathway-related genes to evaluate their associations with overall survival. In individual SNP analysis, 22 variants were significantly associated with overall survival, of which the strongest associations were found for BMP2:rs235756 [hazard ratio (HR) = 1.45; 95% confidence interval (CI), 1.11–1.90] and SMAD3:rs4776342 (HR = 1.25; 95% CI, 1.06–1.47). Fifteen and 18 genetic loci displayed treatment-specific associations for chemotherapy and chemoradiation, respectively, identifying a majority of the cases who would be predicted to respond favorably to a specific treatment regimen. BMP2:rs235753 and a haplotype in SMAD3 were associated with overall survival for both treatment modalities. Cumulative effect analysis showed that multiple risk genotypes had a significant dose-dependent effect on overall survival (Ptrend = 2.44 x 10−15). Survival tree analysis identified subgroups of patients with dramatically different median survival times of 45.39 versus 13.55 months and 18.02 versus 5.89 months for high- and low- risk populations when treated with chemoradiation and chemotherapy, respectively. These results suggest that genetic variations in the TGF-β pathway are potential predictors of overall survival in NSCLC patients treated with platinum-based chemotherapy with or without radiation. PMID:21515830

  1. Thyroid Growth and Cancer

    PubMed Central

    Williams, Dillwyn

    2015-01-01

    It is proposed that most papillary thyroid cancers originate in infancy and childhood, based on the early rise in sporadic thyroid carcinoma incidence, the pattern of radiation-induced risk (highest in those exposed as infants), and the high prevalence of sporadic papillary thyroid cancers in children and adolescents (ultrasound screening after the Fukushima accident). The early origin can be linked to the growth pattern of follicular cells, with a high mitotic rate in infancy falling to very low replacement levels in adult life. The cell of origin of thyroid cancers, the differentiated follicular cell, has a limited growth potential. Unlike cancers originating in stem cells, loss of the usually tight link between differentiation and replicative senescence is required for immortalisation. It is suggested that this loss distinguishes larger clinically significant papillary thyroid cancers from micro-papillary thyroid cancers of little clinical significance. Papillary carcinogenesis can then be divided into 3 stages: (1) initiation, the first mutation in the carcinogenic cascade, for radiation-induced papillary thyroid cancers usually a RET rearrangement, (2) progression, acquisition of the additional mutations needed for low-grade malignancy, and (3) escape, further mutations giving immortality and a higher net growth rate. Most papillary thyroid cancers will not have achieved full immortality by adulthood, and remain as so-called micro-carcinomas with a very low growth rate. The use of the term ‘cancer’ to describe micro-papillary thyroid cancers in older patients encourages overtreatment and alarms patients. Invasive papillary thyroid tumours show a spectrum of malignancy, which at its lowest poses no threat to life. The treatment protocols and nomenclature for small papillary carcinomas need to be reconsidered in the light of the new evidence available, the continuing discovery of smaller lesions, and the model of thyroid carcinogenesis proposed. PMID

  2. Lung cancer nanomedicine: potentials and pitfalls.

    PubMed

    Bölükbas, Deniz Ali; Meiners, Silke

    2015-01-01

    Lung cancer is by far the most common cause of cancer-related deaths in the world. Nanoparticle-based therapies enable targeted drug delivery for lung cancer treatment with increased therapeutic efficiency and reduced systemic toxicity. At the same time, nanomedicine has the potential for multimodal treatment of lung cancer that may involve 'all-in-one' targeting of several tumor-associated cell types in a timely and spatially controlled manner. Therapeutic approaches, however, are hampered by a translational gap between basic scientists, clinicians and pharma industry due to suboptimal animal models and difficulties in scale-up production of nanoagents. This calls for a disease-centered approach with interdisciplinary basic and clinical research teams with the support of pharma industries.

  3. Asbestosis and lobar site of lung cancer

    PubMed Central

    Weiss, W.

    2000-01-01

    OBJECTIVE—To assess the evidence for the hypothesis that lung cancer has a predilection for the lower lobes in workers with asbestosis.
METHOD—A review of the available literature with relevant information.
RESULTS—Six published reports were analysed. In four studies limited to series of cases with diagnoses of asbestosis, three showed lower lobe predominance of lung cancer whereas the fourth study included cases in which the radiographic readings did not meet the usual criterion of profusion for asbestosis. One cohort study showed lower lobe predominance; the other reported only 33% lower lobe cancers compared with 20% in unexposed controls.
CONCLUSION—There is some support for the hypothesis but more studies are needed.


Keywords: asbestos; asbestosis; lung cancer PMID:10769303

  4. Recent advances in personalized lung cancer medicine

    PubMed Central

    Okimoto, Ross A; Bivona, Trever G

    2014-01-01

    The identification of molecular subtypes of non-small-cell lung cancer has transformed the clinical management of this disease. This is best exemplified by the clinical success of targeting the EGFR or ALK with tyrosine kinase inhibitors in the front-line setting. Our ability to further improve patient outcomes with biomarker-based targeted therapies will depend on a more comprehensive genetic platform that can rationally interrogate the cancer genome of an individual patient. Novel technologies, including multiplex genotyping and next-generation sequencing are rapidly evolving and will soon challenge the oncologist with a wealth of genetic information for each patient. Although there are many barriers to overcome, the integration of these genetic platforms into clinical care has the potential to transform the management of lung cancer through improved molecular categorization, patient stratification, and drug development, thereby, improving clinical outcomes through personalized lung cancer medicine. PMID:25506379

  5. Molecular Testing for Selection of Patients With Lung Cancer for Epidermal Growth Factor Receptor and Anaplastic Lymphoma Kinase Tyrosine Kinase Inhibitors: American Society of Clinical Oncology Endorsement of the College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology Guideline

    PubMed Central

    Leighl, Natasha B.; Rekhtman, Natasha; Biermann, William A.; Huang, James; Mino-Kenudson, Mari; Ramalingam, Suresh S.; West, Howard; Whitlock, Sara; Somerfield, Mark R.

    2014-01-01

    Purpose The College of American Pathologists (CAP), the International Association for the Study of Lung Cancer (IASLC), and the Association for Molecular Pathology (AMP) guideline on molecular testing for the selection of patients with lung cancer for epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors was considered for endorsement. Methods American Society of Clinical Oncology (ASCO) staff reviewed the CAP/IASLC/AMP guideline for developmental rigor; an ASCO ad hoc review panel of experts reviewed the guideline content. Results The ASCO panel concurred that the recommendations are clear, thorough, and based on the most relevant scientific evidence in this content area and present options that will be acceptable to patients. The CAP/IASLC/AMP guideline comprises 37 recommendations (evidence grade A or B), expert consensus opinions, or suggestions that address the following five principal questions: (1) When should molecular testing be performed? (2) How should EGFR testing be performed? (3) How should ALK testing be performed? (4) Should other genes be routinely tested in lung adenocarcinoma? (5) How should molecular testing be implemented and operationalized? Conclusion The ASCO review panel endorses the CAP/IASLC/AMP guideline. This guideline represents an important advance toward standardization of EGFR and ALK testing practices and is of major clinical relevance in advancing the care of patients with lung cancer. In the Discussion section, the ASCO review panel highlights three evolving areas: advances in ALK testing methodology, considerations for selecting appropriate populations for molecular testing, and emergence of other targetable molecular alterations. PMID:25311215

  6. Non–Small Cell Lung Cancer: Epidemiology, Risk Factors, Treatment, and Survivorship

    PubMed Central

    Molina, Julian R.; Yang, Ping; Cassivi, Stephen D.; Schild, Steven E.; Adjei, Alex A.

    2009-01-01

    Lung cancer is the leading cause of cancer-related mortality not only in the United States but also around the world. In North America, lung cancer has become more predominant among former than current smokers. Yet in some countries, such as China, which has experienced a dramatic increase in the cigarette smoking rate during the past 2 decades, a peak in lung cancer incidence is still expected. Approximately two-thirds of adult Chinese men are smokers, representing one-third of all smokers worldwide. Non–small cell lung cancer accounts for 85% of all lung cancer cases in the United States. After the initial diagnosis, accurate staging of non–small cell lung cancer using computed tomography or positron emission tomography is crucial for determining appropriate therapy. When feasible, surgical resection remains the single most consistent and successful option for cure. However, close to 70% of patients with lung cancer present with locally advanced or metastatic disease at the time of diagnosis. Chemotherapy is beneficial for patients with metastatic disease, and the administration of concurrent chemotherapy and radiation is indicated for stage III lung cancer. The introduction of angiogenesis, epidermal growth factor receptor inhibitors, and other new anticancer agents is changing the present and future of this disease and will certainly increase the number of lung cancer survivors. We identified studies for this review by searching the MEDLINE and PubMed databases for English-language articles published from January 1, 1980, through January 31, 2008. Key terms used for this search included non–small cell lung cancer, adenocarcinoma, squamous cell carcinoma, bronchioalveolar cell carcinoma, large cell carcinoma, lung cancer epidemiology, genetics, survivorship, surgery, radiation therapy, chemotherapy, targeted therapy, bevacizumab, erlotinib, and epidermal growth factor receptor. PMID:18452692

  7. Fibroblast Growth Factor Receptor 1 (FGFR1), Partly Related to Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) and Microvessel Density, is an Independent Prognostic Factor for Non-Small Cell Lung Cancer

    PubMed Central

    Pu, Dan; Liu, Jiewei; Li, Zhixi; Zhu, Jiang; Hou, Mei

    2017-01-01

    Background This study aimed to explore the correlation between FGFR1 and clinical features, including survival analysis and the promotion of angiogenesis by fibroblast growth factor receptor 1 (FGFR1) and vascular endothelial growth factor receptor 2 (VEGFR2). FGFR1 gene amplification has been found in non-small cell lung cancer (NSCLC). However, the prognostic value of FGFR1 and the correlation between FGFR1 and clinical features are still controversial. Material/Methods A total of 92 patients with NSCLC who underwent R0 resection between July 2006 and July 2008 were enrolled in the study. The expression of FGFR1, VEGFR2, and CD34 was detected by immunohistochemistry. The correlations between the aforementioned markers and the patients’ clinical features were analyzed by the chi-square test. The impact factors of prognosis were evaluated by Cox regression analyses. Results The expression ratios of FGFR1 and VEGFR2 were 26.1% and 43.4%, respectively. The intensity of FGFR1 expression was related to VEGFR2 and histopathology. To some extent, the average microvessel density (MVD) had correlation to the expression of FGFR1 and VGEFR2. The pathological stages III–IV and high expression of FGFR1 were found to be independent prognostic factors. Conclusions The expression intensity of FGFR1 and VEGFR2 was associated with MVD, and the expression of FGFR1 is one of the independent prognostic indicators for NSCLC. PMID:28088809

  8. The role of repair protein Rad51 in synergistic cytotoxicity and mutagenicity induced by epidermal growth factor receptor inhibitor (Gefitinib, Iressa{sup R}) and benzo[a]pyrene in human lung cancer

    SciTech Connect

    Ko, J.-C.; Hong, J.-H.; Wang, L.-H.; Lin, Y.-W.

    2008-05-01

    Rad51 protein is essential for homologous recombination repair of DNA damage, and is over-expressed in chemo- or radioresistant carcinomas. The polycyclic hydrocarbon carcinogen benzo[a]pyrene (B[a]P) affects MAPKs transduction pathways. Gefitinib (Iressa{sup R}, ZD1839) is a selective epidermal growth factor receptor tyrosine kinase inhibitor that blocks growth factor-mediated cell proliferation and ERK1/2 activation. We hypothesized that gefitinib enhances B[a]P-mediated cytotoxicity by decreasing ERK1/2 activation. Exposure of human lung cancer cells to gefitinib decreased B[a]P-elicited ERK1/2 activation and induced Rad51 protein expression. Gefitinib and B[a]P co-treatment decreased Rad51 protein stability by triggering degradation via a 26S proteasome-dependent pathway. Expression of constitutive active MKK1/2 vectors (MKK1/2-CA) rescues the decreased ERK1/2 activity, and restores Rad51 protein level and stability under gefitinib and B[a]P co-treatment. Gefitinib enhances B[a]P-induced growth inhibition, cytotoxicity and mutagenicity. Co-treatment with gefitinib and B[a]P can further inhibit cell growth significantly after depletion of endogenous Rad51 by siRad51 RNA transfection. Enhancement of ERK1/2 activation by MKK1-CA expression decrease B[a]P- and gefitinib-induced cytotoxicity, and B[a]P-induced mutagenicity. Rad51 protein protects lung cancer cells from synergistic cytotoxic and mutagenic effects induced by gefitinib and B[a]P. Suppression of Rad51 protein expression may be a novel lung cancer therapeutic modality to overcome drug resistance to gefitinib.

  9. Intermediate endpoint biomarkers for lung cancer chemoprevention

    NASA Astrophysics Data System (ADS)

    MacAulay, Calum E.; Lam, Stephen; Klein-Parker, Helga; Gazdar, Adi; Guillaud, Martial; Payne, Peter W.; Le Riche, Jean C.; Dawe, Chris; Band, Pierre; Palcic, Branko

    1998-04-01

    Given the demographics of current and ex-smoking populations in North America, lung cancer will be a major problem in the foreseeable future. Early detection and treatment of lung cancer holds great promise for the management of this disease. Unlike cervical cancer, the physical, complete removal/destruction of all dysplastic lesions in the bronchial tree is not possible; however, treatment of the lesions using a chemopreventive agent is. Intermediate biomarkers have been used to screen promising chemopreventive agents for larger population studies. We have examined the natural history of lung cancer development by following a group of subjects at high risk of developing lung cancer using fluorescence endoscopy to identify the areas of abnormality for biopsy. Approximately 900 biopsies have been collected in this fashion and graded by at least two experienced, expert pathologists. Using an interactive version of the Cyto-Savant (Oncometrics Imaging Corp.), cytometric and tissue architectural data were collected from these biopsies. Using only the data from the normal and invasive cancer biopsies, quantitative morphometric and architectural indices were generated and calculated for all the collected biopsies. These indices were compared with Loss of Heterozygosity (LOH) of ten sites commonly associated with cancer. These results and the application of these quantitative measures to two small chemoprevention studies will be reported.

  10. Diagnosis of Lung Cancer by Fractal Analysis of Damaged DNA

    PubMed Central

    Namazi, Hamidreza; Kiminezhadmalaie, Mona

    2015-01-01

    Cancer starts when cells in a part of the body start to grow out of control. In fact cells become cancer cells because of DNA damage. A DNA walk of a genome represents how the frequency of each nucleotide of a pairing nucleotide couple changes locally. In this research in order to study the cancer genes, DNA walk plots of genomes of patients with lung cancer were generated using a program written in MATLAB language. The data so obtained was checked for fractal property by computing the fractal dimension using a program written in MATLAB. Also, the correlation of damaged DNA was studied using the Hurst exponent measure. We have found that the damaged DNA sequences are exhibiting higher degree of fractality and less correlation compared with normal DNA sequences. So we confirmed this method can be used for early detection of lung cancer. The method introduced in this research not only is useful for diagnosis of lung cancer but also can be applied for detection and growth analysis of different types of cancers. PMID:26539245

  11. The early diagnosis of lung cancer.

    PubMed

    Petty, T L

    2001-06-01

    Lung cancer is the most common fatal malignancy in both men and women, both in the United States and elsewhere in the world. Today, lung cancer is most often diagnosed on the basis of symptoms of advanced disease or when chest x-rays are taken for a variety of purposes unrelated to lung cancer detection. Unfortunately, in the United States no society or governmental agency recommends screening, even for patients with high risks, such as smokers with airflow obstruction or people with occupational exposures, including asbestos. The origins of this negative attitude toward lung cancer screening are found in 3 studies sponsored by the National Cancer Institute in the mid-1970s and conducted at Johns Hopkins University School of Medicine, the Mayo Clinic, and the Memorial Sloan-Kettering Center. These studies concluded that early identification of lung cancer through chest x-rays and cytologic diagnosis of sputum did not alter disease-specific mortality. However, patients with earlier stage disease were found through screening, which resulted in a higher resectability rate and improved survival in the screening group compared with a control group of patients receiving ordinary care. Patients in the control group often received annual chest x-rays during the course of this study, which was the standard of care at the time. Thus no true nonscreening control group resulted. The patients at highest risk were not enrolled in this study. No specific amount of pack-years of smoking intensity was required. Only men were screened. The studies were inadequately powered to show an improvement in mortality rate of less than 50%. Ninety percent of lung cancer occurs in smokers. The prevalence of lung cancer is 4 to 6 times greater when smokers have airflow obstruction than with normal airflow, when all other background factors, including smoking history, occupational risk, and family history, are the same. Screening heavy smokers (ie, > or = 30 pack-years) with airflow obstruction

  12. Oncogenic mutation profiling in new lung cancer and mesothelioma cell lines

    PubMed Central

    Lam, David CL; Luo, Susan Y; Deng, Wen; Kwan, Johnny SH; Rodriguez-Canales, Jaime; Cheung, Annie LM; Cheng, Grace HW; Lin, Chi-Ho; Wistuba, Ignacio I; Sham, Pak C; Wan, Thomas SK; Tsao, Sai-Wah

    2015-01-01

    Background Thoracic tumor, especially lung cancer, ranks as the top cancer mortality in most parts of the world. Lung adenocarcinoma is the predominant subtype and there is increasing knowledge on therapeutic molecular targets, namely EGFR, ALK, KRAS, and ROS1, among lung cancers. Lung cancer cell lines established with known clinical characteristics and molecular profiling of oncogenic targets like ALK or KRAS could be useful tools for understanding the biology of known molecular targets as well as for drug testing and screening. Materials and methods Five new cancer cell lines were established from pleural fluid or biopsy tissues obtained from Chinese patients with primary lung adenocarcinomas or malignant pleural mesothelioma. They were characterized by immunohistochemistry, growth kinetics, tests for tumorigenicity, EGFR and KRAS gene mutations, ALK gene rearrangement and OncoSeq mutation profiling. Results These newly established lung adenocarcinoma and mesothelioma cell lines were maintained for over 100 passages and demonstrated morphological and immunohistochemical features as well as growth kinetics of tumor cell lines. One of these new cell lines bears EML4-ALK rearrangement variant 2, two lung cancer cell lines bear different KRAS mutations at codon 12, and known single nucleotide polymorphism variants were identified in these cell lines. Discussion Four new lung adenocarcinoma and one mesothelioma cell lines were established from patients with different clinical characteristics and oncogenic mutation profiles. These characterized cell lines and their mutation profiles will provide resources for exploration of lung cancer and mesothelioma biology with regard to the presence of known oncogenic mutations. PMID:25653542

  13. A Risk Model for Lung Cancer Incidence

    PubMed Central

    Hoggart, Clive; Brennan, Paul; Tjonneland, Anne; Vogel, Ulla; Overvad, Kim; Østergaard, Jane Nautrup; Kaaks, Rudolf; Canzian, Federico; Boeing, Heiner; Steffen, Annika; Trichopoulou, Antonia; Bamia, Christina; Trichopoulos, Dimitrios; Johansson, Mattias; Palli, Domenico; Krogh, Vittorio; Tumino, Rosario; Sacerdote, Carlotta; Panico, Salvatore; Boshuizen, Hendriek; Bueno-de-Mesquita, H. Bas; Peeters, Petra H.M.; Lund, Eiliv; Gram, Inger Torhild; Braaten, Tonje; Rodríguez, Laudina; Agudo, Antonio; Sanchez-Cantalejo, Emilio; Arriola, Larraitz; Chirlaque, Maria-Dolores; Barricarte, Aurelio; Rasmuson, Torgny; Khaw, Kay-Tee; Wareham, Nicholas; Allen, Naomi E.; Riboli, Elio; Vineis, Paolo

    2015-01-01

    Risk models for lung cancer incidence would be useful for prioritizing individuals for screening and participation in clinical trials of chemoprevention. We present a risk model for lung cancer built using prospective cohort data from a general population which predicts individual incidence in a given time period. We build separate risk models for current and former smokers using 169,035 ever smokers from the multicenter European Prospective Investigation into Cancer and Nutrition (EPIC) and considered a model for never smokers. The data set was split into independent training and test sets. Lung cancer incidence was modeled using survival analysis, stratifying by age started smoking, and for former smokers, also smoking duration. Other risk factors considered were smoking intensity, 10 occupational/environmental exposures previously implicated with lung cancer, and single-nucleotide polymorphisms at two loci identified by genome-wide association studies of lung cancer. Individual risk in the test set was measured by the predicted probability of lung cancer incidence in the year preceding last follow-up time, predictive accuracy was measured by the area under the receiver operator characteristic curve (AUC). Using smoking information alone gave good predictive accuracy: the AUC and 95% confidence interval in ever smokers was 0.843 (0.810–0.875), the Bach model applied to the same data gave an AUC of 0.775 (0.737–0.813). Other risk factors had negligible effect on the AUC, including never smokers for whom prediction was poor. Our model is generalizable and straightforward to implement. Its accuracy can be attributed to its modeling of lifetime exposure to smoking. PMID:22496387

  14. Association between diet and lung cancer location.

    PubMed

    Lee, B W; Wain, J C; Kelsey, K T; Wiencke, J K; Christiani, D C

    1998-10-01

    Lung cancers occur more commonly in the upper lobes than in the lower lobes, but its pathophysiologic basis is not well understood. Because numerous studies have reported a consistent inverse relationship between lung cancer risk and intake of certain vegetables and fruits, we hypothesized that the balance between diet-derived protective substances delivered via the circulation and cigarette-derived carcinogenic substances delivered via the airways would be less favorable in the upper lobes compared with the lower lobes, hence accounting for the upper lobe predominance of tumors among smokers. Thus, we examined the association between diet and tumor location in 328 patients with lung cancer. The ratio of upper to lower lobe tumors was 2.5:1.0. In univariate analysis, age, height, weight, sex, race, family history of cancer, education level, tumor histology, calories consumed per day, and intake of animal fat did not differ significantly between patients with upper versus lower lobe tumors. Predictors of tumor location in univariate analysis were family history of lung cancer; smoking history; history of asbestos exposure; and intakes of yellow-orange vegetables, alpha-carotene, beta-carotene, and vitamins A, C, and E. In multivariable logistic regression analysis, the independent predictors of upper lobe tumor location were family history of lung cancer (p = 0.03), history of asbestos exposure (p = 0.02), less intake of yellow-orange vegetables (p < 0.04), and less intake of vitamin E (p = 0.05). Our results show a strong inverse association between upper lobe location of lung cancer and intake of yellow-orange vegetables and vitamin E.

  15. AB036. Comparison of the effectiveness of gefitinib, erlotinib and afatinib in epidermal growth factor receptor mutated tumors of non-small cell lung cancer

    PubMed Central

    Papathanasiou, Maria; Lambaki, Sofia; Porpodis, Konstantinos; Spyratos, Dionysios; Tryfon, Stayros; Zarogoulidis, Paulos; Eleytheriadoy, Ellada; Kontakiotis, Theodoros

    2016-01-01

    The non-small cell lung cancer (NSCLC) accounts approximately 85% of lung cancers and includes predominantly adenocarcinomas, which is the most common type and squamous cell carcinomas. The treatment options include surgery, radiation therapy, and chemotherapy and the decision depends on the patient’s medical status and stage of disease. From 1970 the standard first line treatment for most patients with unresectable NSCLC and good performance status was the use of a combination of chemotherapy regimens and usually cisplatin-based. The most common combination regimens in use at present are platinum based regimens with gemcitabine, with paclitaxel or docetaxel and with vinorelbine combinations. The addition of the recombinant humanized monoclonal antibody bevacizumab that binds to vascular endothelial growth factor (VEGF) to carboplatin and paclitaxel for the treatment of non-squamous advanced NSCLC has demonstrated to increase response rate (RR), progression free survival (PFS) and overall survival (OS) when compared to chemotherapy alone. Despite recent advances with approval of more active chemotherapeutic and anti-angiogenesis agents for stage IV NSCLC, standard therapy can provide only modest clinical benefits with significant toxicities when used in unselected patients. In 2004, the identification of somatic mutations in the epidermal growth factor receptor (EGFR) gene provided the first glimpse of a possible target for a treatment which could maximize clinical outcome in those patients who could benefit from a personalized therapy. Identifying mutations in oncogenes associated with non-squamous NSCLC can help determine which patients are more likely to benefit from a targeted therapy. Such oncogenes include EGFR, KRAS, and ALK. The presence of an EGFR mutation confers a more favorable prognosis and strongly predicts for sensitivity to EGFR tyrosine kinase inhibitors (TKIs) such as erlotinib, gefitinib, and afatinib. The use of EGFR TKIs is based upon the

  16. MicroRNAs in lung cancer

    PubMed Central

    Joshi, Pooja; Middleton, Justin; Jeon, Young-Jun; Garofalo, Michela

    2014-01-01

    MicroRNAs have become recognized as key players in the development of cancer. They are a family of small non-coding RNAs that can negatively regulate the expression of cancer-related genes by sequence-selective targeting of mRNAs, leading to either mRNA degradation or translational repression. Lung cancer is the leading cause of cancer-related death worldwide with a substantially low survival rate. MicroRNAs have been confirmed to play roles in lung cancer development, epithelial-mesenchymal transition and response to therapy. They are also being studied for their future use as diagnostic and prognostic biomarkers and as potential therapeutic targets. In this review we focus on the role of dysregulated microRNA expression in lung tumorigenesis. We also discuss the role of microRNAs in therapeutic resistance and as biomarkers. We further look into the progress made and challenges remaining in using microRNAs for therapy in lung cancer. PMID:25332906

  17. 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. ...

  18. 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. ...

  19. Delaying Chemo After Lung Cancer Surgery? Better Late Than Never

    MedlinePlus

    ... gov/news/fullstory_162926.html Delaying Chemo After Lung Cancer Surgery? Better Late Than Never Patient recovery may ... 6, 2017 FRIDAY, Jan. 6, 2017 (HealthDay News) -- Lung cancer chemotherapy that's been delayed due to slow recovery ...

  20. New genes linked to lung cancer susceptibility in Asian women

    Cancer.gov

    An international group of scientists has identified three genes that predispose Asian women who have never smoked to lung cancer. The discovery of specific genetic variations, which have not previously been associated with lung cancer risk in other popul

  1. Fluorescence imaging of early lung cancer

    NASA Astrophysics Data System (ADS)

    Lam, Stephen; MacAulay, Calum E.; Le Riche, Jean C.; Ikeda, Norihiko; Palcic, Branko

    1995-01-01

    The performance of a fluorescence imaging device was compared with conventional white-light bronchoscopy in 100 patients with lung cancer, 46 patients with resected State I nonsmall cell lung cancer, 10 patients with head and neck cancer, and 67 volunteers who had smoked at least one pack of cigarettes per day for twenty-five years or more. Using differences in tissue autofluorescence between premalignant, malignant and normal tissues, fluorescence bronchoscopy was found to detect more than twice as many moderate-severe dysplasia and carcinoma in situ sites than conventional white-light bronchoscopy. The use of fluorescence imaging to detect small peripheral lung nodules was investigated in a micro metastatic lung model of mice implanted with Lewis lung tumor cells. Fluorescence imaging was found to be able to detect small malignant lung lesions. The use of (delta) -aminolevulinic acid (ALA) to enhance fluorescence detection of CIS was investigated in a patient after oral administration of 60 mg/kg of ALA four hours prior to bronchoscopy, although ALA enhanced the tumor's visibility, multiple sites of false positive fluorescence were observed in areas of inflammation or metaplasia.

  2. Nanomedicine for Treatment of Lung Cancer.

    PubMed

    Hussain, Sajid

    2016-01-01

    Lung cancer is the second most common cancer and the primary cause of cancer-related death in both men and women in the United States and rest of the world. Due to diagnosis at an advanced stage, it is associated with a high mortality in a majority of patients. In recent years, enormous advances have occurred in the development and application of nanotechnology in the detection, diagnosis, and therapy of cancer. This progress has led to the development of the emerging field of "cancer nanomedicine." Nanoparticle-based therapeutic systems have gained immense popularity due to their bioavailability, in vivo stability, intestinal absorption, solubility, sustained and targeted delivery, and therapeutic effectiveness of several anticancer agents. Currently, a plethora of nanocarrier formulations are utilized including lipid-based, polymeric and branched polymeric, metal-based, magnetic, and mesoporous silica. In lung cancer, nanoparticle-based therapeutics is paving the way in the diagnosis, imaging, screening, and treatment of primary and metastatic tumors. The application and expansion of novel nanocarriers for drug delivery is an exciting and challenging research filed, in particular for the delivery of emerging cancer therapies. Some of the current progress and challenges in nanoparticle-based drug delivery systems for lung cancer treatment are discussed.

  3. Multimodal imaging of lung cancer and its microenvironment (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    Hariri, Lida P.; Niederst, Matthew J.; Mulvey, Hillary; Adams, David C.; Hu, Haichuan; Chico Calero, Isabel; Szabari, Margit V.; Vakoc, Benjamin J.; Hasan, Tayyaba; Bouma, Brett E.; Engelman, Jeffrey A.; Suter, Melissa J.

    2016-03-01

    Despite significant advances in targeted therapies for lung cancer, nearly all patients develop drug resistance within 6-12 months and prognosis remains poor. Developing drug resistance is a progressive process that involves tumor cells and their microenvironment. We hypothesize that microenvironment factors alter tumor growth and response to targeted therapy. We conducted in vitro studies in human EGFR-mutant lung carcinoma cells, and demonstrated that factors secreted from lung fibroblasts results in increased tumor cell survival during targeted therapy with EGFR inhibitor, gefitinib. We also demonstrated that increased environment stiffness results in increased tumor survival during gefitinib therapy. In order to test our hypothesis in vivo, we developed a multimodal optical imaging protocol for preclinical intravital imaging in mouse models to assess tumor and its microenvironment over time. We have successfully conducted multimodal imaging of dorsal skinfold chamber (DSC) window mice implanted with GFP-labeled human EGFR mutant lung carcinoma cells and visualized changes in tumor development and microenvironment facets over time. Multimodal imaging included structural OCT to assess tumor viability and necrosis, polarization-sensitive OCT to measure tissue birefringence for collagen/fibroblast detection, and Doppler OCT to assess tumor vasculature. Confocal imaging was also performed for high-resolution visualization of EGFR-mutant lung cancer cells labeled with GFP, and was coregistered with OCT. Our results demonstrated that stromal support and vascular growth are essential to tumor progression. Multimodal imaging is a useful tool to assess tumor and its microenvironment over time.

  4. 4β-Hydroxywithanolide E from Physalis peruviana (golden berry) inhibits growth of human lung cancer cells through DNA damage, apoptosis and G2/M arrest

    PubMed Central

    2010-01-01

    Background The crude extract of the fruit bearing plant, Physalis peruviana (golden berry), demonstrated anti-hepatoma and anti-inflammatory activities. However, the cellular mechanism involved in this process is still unknown. Methods Herein, we isolated the main pure compound, 4β-Hydroxywithanolide (4βHWE) derived from golden berries, and investigated its antiproliferative effect on a human lung cancer cell line (H1299) using survival, cell cycle, and apoptosis analyses. An alkaline comet-nuclear extract (NE) assay was used to evaluate the DNA damage due to the drug. Results It was shown that DNA damage was significantly induced by 1, 5, and 10 μg/mL 4βHWE for 2 h in a dose-dependent manner (p < 0.005). A trypan blue exclusion assay showed that the proliferation of cells was inhibited by 4βHWE in both dose- and time-dependent manners (p < 0.05 and 0.001 for 24 and 48 h, respectively). The half maximal inhibitory concentrations (IC50) of 4βHWE in H1299 cells for 24 and 48 h were 0.6 and 0.71 μg/mL, respectively, suggesting it could be a potential therapeutic agent against lung cancer. In a flow cytometric analysis, 4βHWE produced cell cycle perturbation in the form of sub-G1 accumulation and slight arrest at the G2/M phase with 1 μg/mL for 12 and 24 h, respectively. Using flow cytometric and annexin V/propidium iodide immunofluorescence double-staining techniques, these phenomena were proven to be apoptosis and complete G2/M arrest for H1299 cells treated with 5 μg/mL for 24 h. Conclusions In this study, we demonstrated that golden berry-derived 4βHWE is a potential DNA-damaging and chemotherapeutic agent against lung cancer. PMID:20167063

  5. MALDI Profiling of Human Lung Cancer Subtypes

    PubMed Central

    Nistal, Manuel; Calvo, Enrique; Madero, Rosario; Díaz, Esther; Camafeita, Emilio; de Castro, Javier; López, Juan Antonio; González-Barón, Manuel; Espinosa, Enrique; Fresno Vara, Juan Ángel

    2009-01-01

    Background Proteomics is expected to play a key role in cancer biomarker discovery. Although it has become feasible to rapidly analyze proteins from crude cell extracts using mass spectrometry, complex sample composition hampers this type of measurement. Therefore, for effective proteome analysis, it becomes critical to enrich samples for the analytes of interest. Despite that one-third of the proteins in eukaryotic cells are thought to be phosphorylated at some point in their life cycle, only a low percentage of intracellular proteins is phosphorylated at a given time. Methodology/Principal Findings In this work, we have applied chromatographic phosphopeptide enrichment techniques to reduce the complexity of human clinical samples. A novel method for high-throughput peptide profiling of human tumor samples, using Parallel IMAC and MALDI-TOF MS, is described. We have applied this methodology to analyze human normal and cancer lung samples in the search for new biomarkers. Using a highly reproducible spectral processing algorithm to produce peptide mass profiles with minimal variability across the samples, lineal discriminant-based and decision tree–based classification models were generated. These models can distinguish normal from tumor samples, as well as differentiate the various non–small cell lung cancer histological subtypes. Conclusions/Significance A novel, optimized sample preparation method and a careful data acquisition strategy is described for high-throughput peptide profiling of small amounts of human normal lung and lung cancer samples. We show that the appropriate combination of peptide expression values is able to discriminate normal lung from non-small cell lung cancer samples and among different histological subtypes. Our study does emphasize the great potential of proteomics in the molecular characterization of cancer. PMID:19890392

  6. Oncogenic roles and drug target of CXCR4/CXCL12 axis in lung cancer and cancer stem cell.

    PubMed

    Wang, Zhidong; Sun, Jian; Feng, Yeqian; Tian, Xiaocai; Wang, Bin; Zhou, Yong

    2016-07-01

    Although the great progress has been made in diagnosis and therapeutic in lung cancer, it induces the most cancer death worldwide in both males and females. Chemokines, which have chemotactic abilities, contain up to 50 family members. By binding to G protein-coupled receptors (GPCR), holding seven-transmembrane domain, they function in immune cell trafficking and regulation of cell proliferation, differentiation, activation, and migration, homing under both physiologic and pathologic conditions. The alpha-chemokine receptor CXCR4 for the alpha-chemokine stromal cell-derived-factor-1 (SDF-1) is most widely expressed by tumors. In addition to human tissues of the bone marrow, liver, adrenal glands, and brain, the CXC chemokine SDF-1 or CXCL12 is also highly expressed in lung cancer tissues and is associated with lung metastasis. Lung cancer cells have the capabilities to utilize and manipulate the CXCL12/CXCR system to benefit growth and distant spread. CXCL12/CXCR4 axis is a major culprit for lung cancer and has a crucial role in lung cancer initiation and progression by activating cancer stem cell. This review provides an evaluation of CXCL12/CXCR4 as the potential therapeutic target for lung cancers; it also focuses on the synergistic effects of inhibition of CXCL12/CXCR4 axis and immunotherapy as well as chemotherapy. Together, CXCL12/CXCR4 axis can be a potential therapeutic target for lung cancers and has additive effects with immunotherapy.

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

    ClinicalTrials.gov

    2013-12-16

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

  8. The lung cancer nurse role in the management of paraneoplastic syndromes in lung cancer

    PubMed Central

    2016-01-01

    Paraneoplastic syndromes (PNS) associated with lung cancer are well recognised, are often complex to diagnose, and have minimal evidence to promote nursing and medical management. This paper aims to help guide lung cancer nurses to identify the most common and rarer PNS together with basic clinical management advice to help develop nursing assessments and interventions. The issues regarding the pathway of care at diagnosis together with palliative and supportive care requirements will be addressed and will aim to promote best practice in patients diagnosed with PNS and lung cancer. PMID:27413699

  9. Deubiquitinase USP18 Loss Mislocalizes and Destabilizes KRAS in Lung Cancer.

    PubMed

    Mustachio, Lisa Maria; Lu, Yun; Tafe, Laura J; Memoli, Vincent; Rodriguez-Canales, Jaime; Mino, Barbara; Villalobos, Pamela Andrea; Wistuba, Ignacio; Katayama, Hiroyuki; Hanash, Samir M; Roszik, Jason; Kawakami, Masanori; Cho, Kwang-Jin; Hancock, John F; Chinyengetere, Fadzai; Hu, Shanhu; Liu, Xi; Freemantle, Sarah J; Dmitrovsky, Ethan

    2017-02-27

    KRAS is frequently mutated in lung cancers and is associated with aggressive biology and chemotherapy resistance. Therefore, innovative approaches are needed to treat these lung cancers. Prior work implicated the interferon-stimulated gene 15 (ISG15) deubiquitinase (DUB) USP18 as having anti-neoplastic activity by regulating lung cancer growth and oncoprotein stability. This study demonstrates that USP18 affects the stability of the KRAS oncoprotein. Interestingly, loss of USP18 reduced KRAS expression and engineered gain of USP18 expression increased KRAS protein levels in lung cancer cells. Using the protein synthesis inhibitor cycloheximide (CHX), USP18 knockdown significantly reduced the half-life of KRAS, but gain of USP18 expression significantly increased its stability. Intriguingly, loss of USP18 altered KRAS subcellular localization by mislocalizing KRAS from the plasma membrane. To explore the biological consequences, immunohistochemical (IHC) expression profiles of USP18 were compared in lung cancers of KrasLA2/+ versus cyclin E engineered mouse models. USP18 expression was higher in Kras-driven murine lung cancers, indicating a link between KRAS and USP18 expression in vivo. To solidify this association, loss of Usp18 in KrasLA2/+/Usp18-/- mice was found to significantly reduce lung cancers as compared to parental KrasLA2/+ mice. Lastly, translational relevance was confirmed in a human lung cancer panel by showing USP18 IHC expression was significantly higher in KRAS mutant versus wild-type lung adenocarcinomas.

  10. [MANAGEMENT OF LUNG CANCER IN ELDERLY].

    PubMed

    Leduc, Charlotte; Quoix, Elisabeth

    2015-09-01

    In France, more than 50% of patients diagnosed with lung cancer are elderly but recommendations about their management are scant. Several patient characteristics, as comorbidities, age-related physiological variations of the main body functions, or eventual long-term treatments, are predictive of survival and must consider for therapeutic decision. The Comprehensive Geriatric Assessment (CGA) is the best tool to evaluate elderly with lung cancer and to identify fit patients who are more likely to benefit from standard treatment from frail ones who are candidates for supportive care.

  11. Lung cancer of radiochemical industry workers

    SciTech Connect

    Khokhryakov, V.F.; Romanov, S.A.

    1993-12-31

    The frequency of lung cancers among 2346 radiochemical industry workers exposed to combined external {beta}-{gamma} and internal incorporated plutonium irradiation has been investigated. The results of observation were analyzed assuming the linear relative risk model taking into account prolongation of exposure. On the basis of the obtained data it was shown that life span incidence, of radiation-induced lung cancer is several times greater than 8.5 x 10{sup -3}Sv{sup -1}, which is recommended by ICRP Publication 60 to estimate the carcinogenic risk of organ exposure.

  12. Aryl Hydrocarbon Receptor and Lung Cancer

    PubMed Central

    Tsay, Junchieh J.; Tchou-Wong, Kam-Meng; Greenberg, Alissa K.; Pass, Harvey; Rom, William N.

    2013-01-01

    The leading cause of lung cancer is exposure to cigarette smoke and other environmental pollutants, which include formaldehyde, acrolein, benzene, dioxin, and polycyclic aromatic hydrocarbons (PAHs). PAHs and dioxins are exogenous ligands that directly bind to the aryl hydrocarbon receptor (AhR), a transcription factor that activates xenobiotic metabolism, histone modification (an important step in DNA methylation), and, ultimately, tumorigenesis. Here we summarize the current understanding of AhR and its role in the development of lung cancer, including its influence on cell proliferation, angiogenesis, inflammation, and apoptosis. PMID:23564762

  13. Intercalated Chemotherapy and Epidermal Growth Factor Receptor Inhibitors for Patients With Advanced Non-Small-cell Lung Cancer: A Systematic Review and Meta-analysis.

    PubMed

    La Salvia, Anna; Rossi, Antonio; Galetta, Domenico; Gobbini, Elisa; De Luca, Emmanuele; Novello, Silvia; Di Maio, Massimo

    2017-01-01

    Randomized clinical trials (RCTs) of concurrent epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) plus chemotherapy for unselected patients with advanced non-small-cell lung cancer (NSCLC) produced negative results. Intercalated administration could avoid the reduction of chemotherapy activity due to G1 cell-cycle arrest from EGFR-TKIs. A PubMed search was performed in December 2015 and updated in February 2016. The references from the selected studies were also checked to identify additional eligible trials. Furthermore, the proceedings of the main international meetings were searched from 2010 onward. We included RCTs comparing chemotherapy intercalated with an EGFR-TKI versus chemotherapy alone for patients with advanced NSCLC. Ten RCTs were eligible (6 with erlotinib, 4 with gefitinib): 39% of patients had a known EGFR mutational status, 43% of whom EGFR mutation positive. The intercalated combination was associated with a significant improvement in overall survival (OS; hazard ratio [HR], 0.82; 95% confidence interval [CI], 0.71-0.95; P = .01), progression-free survival (PFS; HR, 0.60; 95% CI, 0.53-0.68; P < .00001), and objective response rate (ORR; odds ratio [OR], 2.70; 95% CI, 2.08-3.49; P < .00001). Considering only first-line trials, similar differences were found in OS (HR, 0.85; 95% CI, 0.72-1.00; P = .05), PFS (HR, 0.63; 95% CI, 0.55-0.73; P < .00001), and ORR (OR, 2.21; 95% CI, 1.65-2.95; P < .00001). In EGFR mutation-positive patients, the addition of an intercalated EGFR-TKI produced a significant benefit in PFS (129 patients; HR, 0.24; 95% CI, 0.16-0.37; P < .00001) and ORR (168 patients; OR, 11.59; 95% CI, 5.54-24.25; P < .00001). In patients with advanced NSCLC, chemotherapy plus intercalated EGFR-TKIs was superior to chemotherapy alone, although a definitive interpretation was jeopardized by the variable proportion of patients with EGFR mutation-positive tumors included.

  14. DUOX1 silencing in lung cancer promotes EMT, cancer stem cell characteristics and invasive properties

    PubMed Central

    Little, A C; Sham, D; Hristova, M; Danyal, K; Heppner, D E; Bauer, R A; Sipsey, L M; Habibovic, A; van der Vliet, A

    2016-01-01

    Dual oxidase 1 (DUOX1) is an oxidant-generating enzyme within the airway epithelium that participates in innate airway host defense and epithelial homeostasis. Recent studies indicate that DUOX1 is suppressed in lung cancers by epigenetic silencing, although the importance of DUOX1 silencing in lung cancer development or progression is unknown. Here we show that loss of DUOX1 expression in a panel of lung cancer cell lines is strongly associated with loss of the epithelial marker E-cadherin. Moreover, RNAi-mediated DUOX1 silencing in lung epithelial cells and the cancer cell line NCI-H292 was found to result in loss of epithelial characteristics/molecular features (altered morphology, reduced barrier function and loss of E-cadherin) and increased mesenchymal features (increased migration, anchorage-independent growth and gain of vimentin/collagen), suggesting a direct contribution of DUOX1 silencing to epithelial-to-mesenchymal transition (EMT), an important feature of metastatic cancer. Conversely, overexpression of DUOX1 in A549 cells was capable of reversing EMT features. DUOX1 silencing in H292 cells also led to enhanced resistance to epidermal growth factor receptor tyrosine kinase inhibitors such as erlotinib, and enhanced levels of cancer stem cell (CSC) markers CD133 and ALDH1. Furthermore, acquired resistance of H292 cells to erlotinib resulted in enhanced EMT and CSC features, as well as loss of DUOX1. Finally, compared with control H292 cells, H292-shDUOX1 cells displayed enhanced invasive features in vitro and in vivo. Collectively, our findings indicate that DUOX1 silencing in lung epithelial cancer cells promotes features of EMT, and may be strongly associated with invasive and metastatic lung cancer. PMID:27694834

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

    PubMed

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

    2016-02-16

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

  16. Liquid biopsy genotyping in lung cancer: ready for clinical utility?

    PubMed

    Huang, Wei-Lun; Chen, Yi-Lin; Yang, Szu-Chun; Ho, Chung-Liang; Wei, Fang; Wong, David T; Su, Wu-Chou; Lin, Chien-Chung

    2017-01-12

    Liquid biopsy is a blood test that detects evidence of cancer cells or tumor DNA in the circulation. Despite complicated collection methods and the requirement for technique-dependent platforms, it has generated substantial interest due, in part, to its potential to detect driver oncogenes such as epidermal growth factor receptor (EGFR) mutants in lung cancer. This technology is advancing rapidly and is being incorporated into numerous EGFR tyrosine kinase inhibitor (EGFR-TKI) development programs. It appears ready for integration into clinical care. Recent studies have demonstrated that biological fluids such as saliva and urine can also be used for detecting EGFR mutant DNA through application other user-friendly techniques. This review focuses on the clinical application of liquid biopsies to lung cancer genotyping, including EGFR and other targets of genotype-directed therapy and compares multiple platforms used for liquid biopsy.

  17. EGFR exon 20 insertion mutation in Japanese lung cancer.

    PubMed

    Sasaki, Hidefumi; Endo, Katsuhiko; Takada, Minoru; Kawahara, Masaaki; Kitahara, Naoto; Tanaka, Hisaichi; Okumura, Meinoshin; Matsumura, Akihide; Iuchi, Keiji; Kawaguchi, Tomoya; Kawano, Osamu; Yukiue, Haruhiro; Yokoyama, Tomoki; Yano, Motoki; Fujii, Yoshitaka

    2007-12-01

    Mutations of the epidermal growth factor receptor (EGFR) gene have been reported in non-small cell lung cancer (NSCLC), especially in female, never smoker patients with adenocarcinoma. Some common somatic mutations in EGFR, including deletion mutations in exon 19 and leucine to arginine substitution at amino acid position 858 (L858R) in exon 21, have been examined for their ability to predict sensitivity to gefitinib or erlotinib. On the other hand, previous report has shown that the insertion mutation at exon 20 is related to gefitinib resistance. We investigated the exon 20 EGFR mutation statuses in 322 surgically treated non-small cell lung cancer cases. Two hundred and five adenocarcinoma cases were included. The presence or absence of EGFR mutations of kinase domains was analyzed by direct sequences. EGFR insertion mutations at exon 20 were found from 7 of 322 (2.17%) lung cancer patients. We also detected the 18 deletion type mutations in exon 19, and 25 L858R type mutations in exon 21. There was a tendency towards higher exon 20 insertion ratio in never smoker (never smoker 4.4% versus smoker 1.3%, p=0.0996) and female (female 4.5% versus male 1.3%, p=0.0917). Two exon 20 insertion cases were treated with gefitinib and failed to response. EGFR insertion mutation in exon 20 could not be ignored from Japanese lung cancers.

  18. Loss of CDH1 up-regulates epidermal growth factor receptor via phosphorylation of YBX1 in non-small cell lung cancer cells.

    PubMed

    Liu, Xianfang; Su, Ling; Liu, Xiangguo

    2013-12-11

    Although loss of CDH1 promotes cancer metastasis by disrupting cell-cell adhesion and inducing transcriptional changes, the functional pathways involved in the loss of CDH1 affecting EGFR expression in lung cancer cells still remain largely unknown. In this study, we report that down-regulation of CDH1 promoted EGFR transcription through activation of YBX1. Furthermore, knockdown of CDH1 activated the AKT signaling pathway, and inhibition of AKT suppressed the phosphorylation of YBX1 and the up-regulation of EGFR induced by CDH1 loss. These data demonstrate that loss of CDH1 induces EGFR expression via phospho-YBX1, which is activated through the AKT signaling pathway.

  19. Integrating smoking cessation into lung cancer screening programs.

    PubMed

    Pua, Bradley B; Dou, Eda; O'Connor, Katherine; Crawford, Carolyn B

    2016-01-01

    Early detection through low-dose computed tomographic screening for lung cancer and implementation of smoking cessation can reduce mortality related to lung cancer. While studies delineating the relationship between smoking cessation strategies and lung cancer screening programs remain sparse, we aim to review available data on their importance both individually and synergistically. Strategies and obstacles for implementation are also discussed.

  20. Magnitude of asbestos-related lung cancer mortality in Italy

    PubMed Central

    Marinaccio, A; Scarselli, A; Binazzi, A; Mastrantonio, M; Ferrante, P; Iavicoli, S

    2008-01-01

    An ecological study, based on a data set containing all lung and pleural cancer deaths in each Italian municipality in the period 1980–2001, was performed. The pleural to lung cancer ratio was estimated to be 1 : 1 and 3% (around 700) of all male lung cancer deaths were found to be asbestos-related. PMID:18577986

  1. Chemoprevention of lung cancer by tea.

    PubMed

    Clark, Julie; You, Ming

    2006-02-01

    Tea is the second only to water as the most consumed beverage in the world. Both green and black teas have been studied for their health benefits for a variety of diseases, particularly cancer. Lung cancer is the predominant cause of cancer mortality in developed countries. Smokers' risk of lung cancer is 20 times that of persons who have never smoked. Epidemiological studies on the cancer-preventive effects of tea produce inconsistent results, which could in part be attributed to the lack of a universal standard for tea preparations. However, most animal studies indicate that tea has strong chemopreventive effects against lung tumorigenesis. The reported mechanisms for chemopreventive activity of green tea are antioxidation, induction of phase II enzymes, inhibition of TNFalpha expression and release, inhibition of cell proliferation, and induction of apoptosis. Cell cycle arrest and apoptosis induced by green tea are probably the two most significant factors. Future studies are needed to determine how green tea affects the genes associated with cell cycle regulation and apoptosis during the mouse lung carcinogenesis process.

  2. 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

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

    ClinicalTrials.gov

    2017-03-28

    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

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

    PubMed Central

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

    2015-01-01

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

  5. Risks of Lung Cancer Screening

    MedlinePlus

    ... medical care even if there are symptoms. False-positive test results can occur. Screening test results may ... even though no cancer is present. A false-positive test result (one that shows there is cancer ...

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

    PubMed Central

    2012-01-01

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

  7. Biomarkers and Targeted Systemic Therapies in Advanced Non-Small Cell Lung Cancer

    PubMed Central

    Kumar, Mukesh; Vinicius, Ernani; Owonikoko, Taofeek K.

    2015-01-01

    The last decade has witnessed significant growth in therapeutic options for patients diagnosed with lung cancer. This is due in major part to our improved technological ability to interrogate the genomics of cancer cells, which has enabled the development of biologically rational anticancer agents. The recognition that lung cancer is not a single disease entity dates back many decades to the histological subclassification of malignant neoplasms of the lung into subcategories of small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). While SCLC continues to be regarded as a single histologic and therapeutic category, the NSCLC subset has undergone additional subcategorizations with distinct management algorithms for specific histologic and molecular subtypes. The defining characteristics of these NSCLC subtypes have evolved into important tools for prognosis and for predicting the likelihood of benefit when patients are treated with anticancer agents. PMID:26187108

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

    PubMed Central

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

    2016-01-01

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

  9. Prognosis of Lung Cancer: Heredity or Environment

    DTIC Science & Technology

    2015-06-01

    diagnosed at distant stage than whites (57 versus 45%; p = 0.03). In multivariable analyses adjusted for pack-years of smoking, age, body mass index, health ...cancer in under- served populations,14 understanding lung cancer prognosis in these populations is necessary for targeted public health interventions...Division of Epidemiology, Department of Medicine, ‡Institute for Medicine and Public Health , Department of Medicine, Vanderbilt University Medical

  10. Role of high expression levels of STK39 in the growth, migration and invasion of non-small cell type lung cancer cells

    PubMed Central

    Xiong, Liwen; Yu, Xiaobo; Chen, Xi; Lin, Qiang

    2016-01-01

    Non-small cell type lung cancer (NSCLC) is the most common malignancy and the leading cause of cancer related mortality. In this study, serine/threonine kinase 39 (STK39) was identified as an up-regulated gene in NSCLC tissues by next-generation RNA sequencing. Although STK39 gene polymorphisms may be prognostic of overall survival in patients with early stage NSCLC, the roles of STK39 in NSCLC cancer are poorly understood. In the current study, Genome Set Enrichment Analysis (GSEA) on the RNA-seq data of NSCLC specimens indicated that cancer-related process and pathways, including metastasis, cell cycle, apoptosis and p38 pathway, were significantly correlated with STK39 expression. STK39 expression was significantly increased in NSCLC cases and its protein expression was positively correlated with the poor tumor stage, large tumor size, advanced lymphnode metastasis and poor prognosis. Down-regulation of STK39 in NSCLC cells significantly decreased cell proliferation by blocking of cell cycle and inducing apoptosis. We also found that STK39 knockdown in NSCLC cells remarkably repressed cell migration and invasion. On the contrary, overexpression of STK39 in NSCLC cells had inverse effects on cell behaviors. Taken together, STK39 acts as a tumor oncogene in NSCLC and can be a potential biomarker of carcinogenesis. PMID:27542260

  11. Mitochondrial DNA Mutations in Respiratory Complex-I in Never-Smoker Lung Cancer Patients Contribute to Lung Cancer Progression and associated with EGFR gene mutation

    PubMed Central

    Dasgupta, Santanu; Soudry, Ethan; Mukhopadhyay, Nitai; Shao, Chunbo; Yee, John; Lam, Stephan; Lam, Wan; Zhang, Wei; Gazdar, Adi F; Fisher, Paul B; Sidransky, David

    2011-01-01

    Mitochondrial DNA (mtDNA) mutations were reported in different cancers. However, the nature and role of mtDNA mutation in never-smoker lung cancer patients including patients with EGFR and KRAS gene mutation are unknown. In the present study, we sequenced entire mitochondrial genome (16.5 kb) in matched normal and tumors obtained from 30 never-smoker and 30 current-smoker lung cancer patients, and determined the mtDNA content. All the patients’ samples were sequenced for KRAS (exon 2) and EGFR (exon 19 and 21) gene mutation. The impact of forced overexpression of a respiratory complex-I gene mutation was evaluated in a lung cancer cell line. We observed significantly higher (P=0.006) mtDNA mutation in the never-smokers compared to the current-smoker lung cancer patients. MtDNA mutation was significantly higher (P=0.026) in the never-smoker Asian compared to the current-smoker Caucasian patients’ population. MtDNA mutation was significantly (P=0.007) associated with EGFR gene mutation in the never-smoker patients. We also observed a significant increase (P=0.037) in mtDNA content among the never-smoker lung cancer patients. The majority of the coding mtDNA mutations targeted respiratory complex-I and forced overexpression of one of these mutations resulted in increased in vitro proliferation, invasion and superoxide production in lung cancer cells. We observed a higher prevalence and new relationship between mtDNA alterations among never-smoker lung cancer patients and EGFR gene mutation. Moreover, a representative mutation produced strong growth effects after forced overexpression in lung cancer cells. Signature mtDNA mutations provide a basis to develop novel biomarkers and therapeutic strategies for never-smoker lung cancer patients. PMID:21830212

  12. Interventional Analgesic Management of Lung Cancer Pain

    PubMed Central

    Hochberg, Uri; Elgueta, Maria Francisca; Perez, Jordi

    2017-01-01

    Lung cancer is one of the four most prevalent cancers worldwide. Comprehensive patient care includes not only adherence to clinical guidelines to control and when possible cure the disease but also appropriate symptom control. Pain is one of the most prevalent symptoms in patients diagnosed with lung cancer; it can arise from local invasion of chest structures or metastatic disease invading bones, nerves, or other anatomical structures potentially painful. Pain can also be a consequence of therapeutic approaches like surgery, chemotherapy, or radiotherapy. Conventional medical management of cancer pain includes prescription of opioids and coadjuvants at doses sufficient to control the symptoms without causing severe drug effects. When an adequate pharmacological medical management fails to provide satisfactory analgesia or when it causes limiting side effects, interventional cancer pain techniques may be considered. Interventional pain management is devoted to the use of invasive techniques such as joint injections, nerve blocks and/or neurolysis, neuromodulation, and cement augmentation techniques to provide diagnosis and treatment of pain syndromes resistant to conventional medical management. Advantages of interventional approaches include better analgesic outcomes without experiencing drug-related side effects and potential for opioid reduction thus avoiding central side effects. This review will describe various pain syndromes frequently described in lung cancer patients and those interventional techniques potentially indicated for those cases. PMID:28261561

  13. Outdoor air pollution and lung cancer.

    PubMed Central

    Cohen, A J

    2000-01-01

    In the 1950s evidence of an ongoing epidemic of lung cancer in the United States and Western Europe led researchers to examine the role of outdoor air pollution, which was considered by some to be a likely cause. Although epidemiologic research quickly identified the central role of cigarette smoking in this epidemic, and despite progress in reducing outdoor air pollution in Western industrialized countries, concerns that ambient air pollution is causing lung cancer have persisted to the present day. This concern is based on the fact that known carcinogens continue to be released into outdoor air from industrial sources, power plants, and motor vehicles, and on a body of epidemiologic research that provides some evidence for an association between outdoor air pollution and lung cancer. This article reviews the epidemiologic evidence for this association and discusses the limitations of current studies for estimating the lung cancer risk in the general population. It also identifies research needs and suggests possible approaches to addressing outstanding questions. PMID:10931793

  14. [Stereotactic ablative irradiation for lung cancer].

    PubMed

    Antoni, D; Srour, I; Noël, G; Mornex, F

    2014-01-01

    Stereotactic radiotherapy for lung cancer is a technique that is now well established in the therapeutic arsenal. Protocols are effective, with very high local control rate and an acceptable rate of survival if one takes into account the patient's age and comorbidities. Complications are rare. This review of the literature analyses the whole process of the therapeutic indications and future prospects.

  15. Gene variant linked to lung cancer risk

    Cancer.gov

    A variation of the gene NFKB1, called rs4648127, is associated with an estimated 44 percent reduction in lung cancer risk. When this information, derived from samples obtained as part of a large NCI-sponsored prevention clinical trial, was compared with d

  16. Lung cancer from passive smoking at work.

    PubMed Central

    Wells, A J

    1998-01-01

    OBJECTIVES: This study was undertaken to determine whether exposure at work to environmental tobacco smoke is associated with an increased risk of lung cancer. METHODS: Data from 14 studies providing information on lung cancer and exposure to environmental tobacco smoke at work were examined. Six quality criteria were developed for determining usable data. A meta-analysis was performed to obtain a combined risk for those data that met the quality restrictions. RESULTS: Five studies met the quality standards. Their combined relative risk was 1.39 (95% confidence interval [CI] = 1.15, 1.68) based on 835 lung cancer cases. In various meta-analyses prepared by tobacco industry employees or consultants, no increase in risk was found. The main reason for this difference is that the earlier analysts failed to find errors in 2 underlying studies that resulted in overweighting of the odds ratios from those studies, both of which were less than unity. CONCLUSIONS: When appropriate cognizance is taken of the quality of data inputs, the increase in lung cancer risk from workplace exposure to environmental tobacco smoke is about the same as that from household exposure. PMID:9663148

  17. Elevated SP-1 Transcription Factor Expression and Activity Drives Basal and Hypoxia-induced Vascular Endothelial Growth Factor (VEGF) Expression in Non-Small Cell Lung Cancer

    PubMed Central

    Deacon, Karl; Onion, David; Kumari, Rajendra; Watson, Susan A.; Knox, Alan J.

    2012-01-01

    VEGF plays a central role in angiogenesis in cancer. Non-small cell lung cancer (NSCLC) tumors have increased microvascular density, localized hypoxia, and high VEGF expression levels; however, there is a lack of understanding of how oncogenic and tumor microenvironment changes such as hypoxia lead to greater VEGF expression in lung and other cancers. We show that NSCLC cells secreted higher levels of VEGF than normal airway epithelial cells. Actinomycin D inhibited all NSCLC VEGF secretion, and VEGF minimal promoter-luciferase reporter constructs were constitutively active until the last 85 base pairs before the transcription start site containing three SP-1 transcription factor-binding sites; mutation of these VEGF promoter SP-1-binding sites eliminated VEGF promoter activity. Furthermore, dominant negative SP-1, mithramycin A, and SP-1 shRNA decreased VEGF promoter activity, whereas overexpression of SP-1 increased VEGF promoter activity. Chromatin immunoprecipitation assays demonstrated SP-1, p300, and PCA/F histone acetyltransferase binding and histone H4 hyperacetylation at the VEGF promoter in NSCLC cells. Cultured NSCLC cells expressed higher levels of SP-1 protein than normal airway epithelial cells, and double-fluorescence immunohistochemistry showed a strong correlation between SP-1 and VEGF in human NSCLC tumors. In addition, hypoxia-driven VEGF expression in NSCLC cells was SP-1-dependent, with hypoxia increasing SP-1 activity and binding to the VEGF promoter. These studies are the first to demonstrate that overexpression of SP-1 plays a central role in hypoxia-induced VEGF secretion. PMID:22992725

  18. Lung Cancer Risk Models for Screening (R package: lcrisks)

    Cancer.gov

    In both the absence and presence of screening, the R package lcrisks, calculates individual risks of lung cancer and lung cancer death based on covariates: age, education, sex, race, smoking intensity/duration/quit-years, Body Mass Index, family history of lung-cancer, and self-reported emphysema. In the presence of CT screening akin to the NLST (3 yearly screens, 5 years of follow-up), it uses the covariates to estimate risk of false-positive CT screen as well as the reduction in risk of lung cancer death and increase in risk of lung cancer screening.

  19. Lung Cancer Treatment | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  20. The haematopoietic specific signal transducer Vav1 is aberrantly expressed in lung cancer and plays a role in tumourigenesis.

    PubMed

    Lazer, Galit; Idelchuk, Yulia; Schapira, Vered; Pikarsky, Eli; Katzav, Shulamit

    2009-09-01

    Lung cancer is the leading cause of cancer death worldwide. The spectrum of aberrations affecting signalling pathways in lung cancer pathogenesis has not been fully elucidated. Physiological expression of Vav1 is restricted to the haematopoietic system, where its best-known function is as a GDP/GTP nucleotide exchange factor for Rho/RacGTPases, an activity strictly controlled by tyrosine phosphorylation downstream of cell surface receptors. Here we find Vav1 expression in 42% of 78 lung cancer cell lines analysed. Moreover, immunohistochemical analysis of primary human lung cancer tissue samples revealed Vav1 expression in 26/59 malignant samples, including adenocarcinoma, squamous cell carcinoma and bronchioloalveolar carcinoma. Stronger Vav1 staining was associated with larger tumour size. siRNA-mediated knockdown of Vav1 in lung cancer cells reduced proliferation in agar and tumour growth in nude mice, while control siRNA had no effect, suggesting that Vav1 plays a critical role in the tumorigenicity of lung cancer cells. Vav1 is tyrosine-phosphorylated in lung cancer cells following activation by the growth factors EGF and TGFalpha, suggesting its participation in signalling events in these cells. Depletion of Vav1 reduced Rac-GTP activation and decreased expression of TGFalpha, an autocrine growth factor. These data suggest that Vav1 plays a role in the neoplastic process in lung cancer, identifying it as a potential therapeutic target for lung cancer therapy.

  1. Molecular alterations in non-small-cell lung cancer: perspective for targeted therapy and specimen management for the bronchoscopist.

    PubMed

    Czarnecka-Kujawa, Kasia; Yasufuku, Kazuhiro

    2014-11-01

    Major advances have occurred over the past decade in our understanding of lung cancer pathobiology. Increasing knowledge of molecular aberrations in lung cancer, specifically the discovery of two driver genes in pharmacologically targetable tyrosine kinases involved in growth factor receptor signalling, epidermal growth factor receptor and anaplastic lymphoma kinase, has been of major therapeutic and prognostic importance. This discovery has allowed for new, personalized approach to the management of lung cancer. Recognizing the importance of molecular signatures of lung cancer, the College of American Pathologists, International Association for the Study of Lung Cancer and Association for Molecular Pathology released the first guidelines for molecular testing in lung cancer. The introduction of minimally invasive needle techniques for the evaluation of lung cancer patients, such as endobronchial ultrasound transbronchial needle aspiration and oesophageal ultrasound-fine-needle aspiration, has revolutionized the way lung cancer patients are assessed. Samples obtained using the minimally invasive needle approaches have been shown to be sufficient not only for routine molecular testing but also for multigenic analysis. This allows bronchoscopist to assume an increasingly important role in the diagnostic workup of patients with lung cancer at all stages of the disease and contribute to personalizing the care of lung cancer patients.

  2. Establishment of a human lung cancer cell line with high metastatic potential to multiple organs: gene expression associated with metastatic potential in human lung cancer.

    PubMed

    Nakano, Tetsuhiro; Shimizu, Kimihiro; Kawashima, Osamu; Kamiyoshihara, Mitsuhiro; Kakegawa, Seiichi; Sugano, Masayuki; Ibe, Takashi; Nagashima, Toshiteru; Kaira, Kyoichi; Sunaga, Noriaki; Ohtaki, Youichi; Atsumi, Jun; Takeyoshi, Izumi

    2012-11-01

    Convenient and reliable multiple organ metastasis model systems might contribute to understanding the mechanism(s) of metastasis of lung cancer, which may lead to overcoming metastasis and improvement in the treatment outcome of lung cancer. We isolated a highly metastatic subline, PC14HM, from the human pulmonary adenocarcinoma cell line, PC14, using an in vivo selection method. The expression of 34,580 genes was compared between PC14HM and parental PC14 by cDNA microarray analysis. Among the differentially expressed genes, expression of four genes in human lung cancer tissues and adjacent normal lung tissues were compared using real-time reverse transcription polymerase chain reaction. Although BALB/c nude mice inoculated with parental PC14 cells had few metastases, almost all mice inoculated with PC14HM cells developed metastases in multiple organs, including the lung, bone and adrenal gland, the same progression seen in human lung cancer. cDNA microarray analysis revealed that 981 genes were differentially (more than 3-fold) expressed between the two cell lines. Functional classification revealed that many of those genes were associated with cell growth, cell communication, development and transcription. Expression of three upregulated genes (HRB-2, HS3ST3A1 and RAB7) was higher in human cancer tissue compared to normal lung tissue, while expression of EDG1, which was downregulated, was lower in the cancer tissue compared to the normal lung. These results suggest that the newly established PC14HM cell line may provide a mouse model of widespread metastasis of lung cancer. This model system may provide insights into the key genetic determinants of widespread metastasis of lung cancer.

  3. Vaccine Therapy in Treating Patients With Colon, Pancreatic, or Lung Cancer

    ClinicalTrials.gov

    2015-04-27

    Recurrent Colon Cancer; Extensive Stage Small Cell Lung Cancer; Stage III Pancreatic Cancer; Stage III Rectal Cancer; Limited Stage Small Cell Lung Cancer; Recurrent Pancreatic Cancer; Recurrent Rectal Cancer; Stage III Non-small Cell Lung Cancer; Stage I Pancreatic Cancer; Stage II Non-small Cell Lung Cancer; Stage IVB Pancreatic Cancer; Stage II Pancreatic Cancer; Stage III Colon Cancer; Stage IVA Pancreatic Cancer

  4. MicroRNA-346 facilitates cell growth and metastasis, and suppresses cell apoptosis in human non-small cell lung cancer by regulation of XPC/ERK/Snail/E-cadherin pathway

    PubMed Central

    Sun, Cheng-Cao; Li, Shu-Jun; Yuan, Zhan-Peng; Li, De-Jia

    2016-01-01

    Determinants of growth and metastasis in cancer remain of great interest to define. MicroRNAs (miRNAs) have frequently emerged as tumor metastatic regulator by acting on multiple signaling pathways. Here we report the definition of miR-346 as a novel oncogenic microRNA that facilitates non-small cell lung cancer (NSCLC) cell growth and metastasis. XPC, an important DNA damage recognition factor in nucleotide excision repair was defined as a target for down-regulation by miR-346, functioning through direct interaction with the 3′-UTR of XPC mRNA. Blocking miR-346 by an antagomiR was sufficient to inhibit NSCLC cell growth and metastasis, an effect that could be phenol-copied by RNAi-mediated silencing of XPC. In vivo studies established that miR-346 overexpression was sufficient to promote tumor growth by A549 cells in xenografts mice, relative to control cells. Overall, our results defined miR-346 as an oncogenic miRNA in NSCLC, the levels of which contributed to tumor growth and invasive aggressiveness. PMID:27777383

  5. Compound Library Screening Identified Cardiac Glycoside Digitoxin as an Effective Growth Inhibitor of Gefitinib-Resistant Non-Small Cell Lung Cancer via Downregulation of α-Tubulin and Inhibition of Microtubule Formation.

    PubMed

    Zhang, Yi-Ze; Chen, Xi; Fan, Xing-Xing; He, Jian-Xing; Huang, Jun; Xiao, Da-Kai; Zhou, Yan-Ling; Zheng, Sen-You; Xu, Jia-Hui; Yao, Xiao-Jun; Liu, Liang; Leung, Elaine Lai-Han

    2016-03-18

    Non-small-cell lung cancer (NSCLC) dominates over 85% of all lung cancer cases. Epidermal growth factor receptor (EGFR) activating mutation is a common situation in NSCLC. In the clinic, molecular-targeting with Gefitinib as a tyrosine kinase inhibitor (TKI) for EGFR downstream signaling is initially effective. However, drug resistance frequently happens due to additional mutation on EGFR, such as substitution from threonine to methionine at amino acid position 790 (T790M). In this study, we screened a traditional Chinese medicine (TCM) compound library consisting of 800 single compounds in TKI-resistance NSCLC H1975 cells, which contains substitutions from leucine to arginine at amino acid 858 (L858R) and T790M mutation on EGFR. Attractively, among these compounds there are 24 compounds CC50 of which was less than 2.5 μM were identified. We have further investigated the mechanism of the most effective one, Digitoxin. It showed a significantly cytotoxic effect in H1975 cells by causing G2 phase arrest, also remarkably activated 5' adenosine monophosphate-activated protein kinase (AMPK). Moreover, we first proved that Digitoxin suppressed microtubule formation through decreasing α-tubulin. Therefore, it confirmed that Digitoxin effectively depressed the growth of TKI-resistance NSCLC H1975 cells by inhibiting microtubule polymerization and inducing cell cycle arrest.

  6. The MEK-Inhibitor Selumetinib Attenuates Tumor Growth and Reduces IL-6 Expression but Does Not Protect against Muscle Wasting in Lewis Lung Cancer Cachexia.

    PubMed

    Au, Ernie D; Desai, Aditya P; Koniaris, Leonidas G; Zimmers, Teresa A

    2016-01-01

    Cachexia, or wasting of skeletal muscle and fat, afflicts many patients with chronic diseases including cancer, organ failure, and AIDS. Muscle wasting reduces quality of life and decreases response to therapy. Cachexia is caused partly by elevated inflammatory cytokines, including interleukin-6 (IL-6). Others and we have shown that IL-6 alone is sufficient to induce cachexia both in vitro and in vivo. The mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) inhibitor Selumetinib has been tested in clinical trials for various cancers. Moreover, Selumetinib has also been shown to inhibit the production of IL-6. In a retrospective analysis of a phase II clinical trial in advanced cholangiocarcinoma, patients treated with Selumetinib experienced significant gains in skeletal muscle vs. patients receiving standard therapy. However, the use of Selumetinib as a treatment for cachexia has yet to be investigated mechanistically. We sought to determine whether MEK inhibition could protect against cancer-induced cachexia in mice. In vitro, Selumetinib induced C2C12 myotube hypertrophy and nuclear accretion. Next we tested Selumetinib in the Lewis lung carcinoma (LLC) model of cancer cachexia. Treatment with Selumetinib reduced tumor mass and reduced circulating and tumor IL-6; however MEK inhibition did not preserve muscle mass. Similar wasting was seen in limb muscles of Selumetinib and vehicle-treated LLC mice, while greater fat and carcass weight loss was observed with Selumetinib treatment. As well, Selumetinib did not block wasting in C2C12 myotubes treated with LLC serum. Taken together, out results suggest that this MEK inhibitor is not protective in LLC cancer cachexia despite lowering IL-6 levels, and further that it might exacerbate tumor-induced weight loss. Differences from other studies might be disease, species or model-specific.

  7. The MEK-Inhibitor Selumetinib Attenuates Tumor Growth and Reduces IL-6 Expression but Does Not Protect against Muscle Wasting in Lewis Lung Cancer Cachexia

    PubMed Central

    Au, Ernie D.; Desai, Aditya P.; Koniaris, Leonidas G.; Zimmers, Teresa A.

    2017-01-01

    Cachexia, or wasting of skeletal muscle and fat, afflicts many patients with chronic diseases including cancer, organ failure, and AIDS. Muscle wasting reduces quality of life and decreases response to therapy. Cachexia is caused partly by elevated inflammatory cytokines, including interleukin-6 (IL-6). Others and we have shown that IL-6 alone is sufficient to induce cachexia both in vitro and in vivo. The mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) inhibitor Selumetinib has been tested in clinical trials for various cancers. Moreover, Selumetinib has also been shown to inhibit the production of IL-6. In a retrospective analysis of a phase II clinical trial in advanced cholangiocarcinoma, patients treated with Selumetinib experienced significant gains in skeletal muscle vs. patients receiving standard therapy. However, the use of Selumetinib as a treatment for cachexia has yet to be investigated mechanistically. We sought to determine whether MEK inhibition could protect against cancer-induced cachexia in mice. In vitro, Selumetinib induced C2C12 myotube hypertrophy and nuclear accretion. Next we tested Selumetinib in the Lewis lung carcinoma (LLC) model of cancer cachexia. Treatment with Selumetinib reduced tumor mass and reduced circulating and tumor IL-6; however MEK inhibition did not preserve muscle mass. Similar wasting was seen in limb muscles of Selumetinib and vehicle-treated LLC mice, while greater fat and carcass weight loss was observed with Selumetinib treatment. As well, Selumetinib did not block wasting in C2C12 myotubes treated with LLC serum. Taken together, out results suggest that this MEK inhibitor is not protective in LLC cancer cachexia despite lowering IL-6 levels, and further that it might exacerbate tumor-induced weight loss. Differences from other studies might be disease, species or model-specific. PMID:28149280

  8. Deaths in Canada from lung cancer due to involuntary smoking.

    PubMed Central

    Wigle, D T; Collishaw, N E; Kirkbride, J; Mao, Y

    1987-01-01

    Recently published evidence indicates that involuntary smoking causes an increased risk of lung cancer among nonsmokers. Information was compiled on the proportion of people who had never smoked among victims of lung cancer, the risk of lung cancer for nonsmokers married to smokers and the prevalence of such exposure. On the basis of these data we estimate that 50 to 60 of the deaths from lung cancer in Canada in 1985 among people who had never smoked were caused by spousal smoking; about 90% occurred in women. The total number of deaths from lung cancer attributable to exposure to tobacco smoke from spouses and other sources (mainly the workplace) was derived by applying estimated age- and sex-specific rates of death from lung cancer attributable to such exposure to the population of Canadians who have never smoked; about 330 deaths from lung cancer annually are attributable to such exposure. PMID:3567810

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

    PubMed

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

    2016-06-07

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

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

    PubMed Central

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

    2016-01-01

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

  11. Smoking, p53 mutation, and lung cancer.

    PubMed

    Gibbons, Don L; Byers, Lauren A; Kurie, Jonathan M

    2014-01-01

    This issue marks the 50th anniversary of the release of the U.S. Surgeon General's Report on Smoking and Health. Perhaps no other singular event has done more to highlight the effects of smoking on the development of cancer. Tobacco exposure is the leading cause of cancers involving the oral cavity, conductive airways, and the lung. Owing to the many carcinogens in tobacco smoke, smoking-related malignancies have a high genome-wide burden of mutations, including in the gene encoding for p53. The p53 protein is the most frequently mutated tumor suppressor in cancer, responsible for a range of critical cellular functions that are compromised by the presence of a mutation. Herein, we review the epidemiologic connection between tobacco exposure and cancer, the molecular basis of p53 mutation in lung cancer, and the normal molecular and cellular roles of p53 that are abrogated during lung tumor development and progression as defined by in vitro and in vivo studies. We also consider the therapeutic potential of targeting mutant p53 in a clinical setting based upon the cellular role of mutant p53 and data from genetic murine models.

  12. Breath sensors for lung cancer diagnosis.

    PubMed

    Adiguzel, Yekbun; Kulah, Haluk

    2015-03-15

    The scope of the applications of breath sensors is abundant in disease diagnosis. Lung cancer diagnosis is a well-fitting health-related application of this technology, which is of utmost importance in the health sector, because lung cancer has the highest death rate among all cancer types, and it brings a high yearly global burden. The aim of this review is first to provide a rational basis for the development of breath sensors for lung cancer diagnostics from a historical perspective, which will facilitate the transfer of the idea into the rapidly evolving sensors field. Following examples with diagnostic applications include colorimetric, composite, carbon nanotube, gold nanoparticle-based, and surface acoustic wave sensor arrays. These select sensor applications are widened by the state-of-the-art developments in the sensors field. Coping with sampling sourced artifacts and cancer staging are among the debated topics, along with the other concerns like proteomics approaches and biomimetic media utilization, feature selection for data classification, and commercialization.

  13. MiR-338-3p inhibits the growth and invasion of non-small cell lung cancer cells by targeting IRS2

    PubMed Central

    Zhang, Peng; Shao, Guoguang; Lin, Xingyu; Liu, Yunpeng; Yang, Zhiguang

    2017-01-01

    MicroRNA-338-3p (miR-338-3p) has recently been reported to have anti-cancer efficacy in several types of cancers. However, its biological function and underlying mechanism involved in modulation of human non-small cell lung cancer (NSCLC) remain largely unknown. The present study was designed to investigate the function and underlying mechanism of miR-338-3p in human NSCLC tissues and cell lines. We demonstrated that miR-338-3p was significantly decreased in NSCLC tissues and cell lines, and negatively correlated with advanced and tumor-node-metastasis (TNM) stage and lymph node metastasis (both P<0.01). Transient overexpression of miR-338-3p by transfecting with miR-338-3p mimic significantly suppressed NSCLC cell proliferation, migration, invasion and induced apoptosis and cell cycle at G1 phase. Additionally, insulin receptor substrate 2 (IRS2), a known oncogene, was identified as a potential target gene of miR-338-3p. Subsequent investigations found a negative correlation between the expression of miR-338-3p and IRS2 in NSCLC tissues. Furthermore, overexpression of IRS2 reversed the effects of miR-338-3p in NSCLC cells on cell proliferation, cycle, apoptosis, migration, invasion. These findings suggested that miR-338-3p might act as a tumor suppressor by directly targeting IRS2 in NSCLC. PMID:28123847

  14. Cationic lipid guided short-hairpin RNA interference of annexin A2 attenuates tumor growth and metastasis in a mouse lung cancer stem cell model

    PubMed Central

    Andey, Terrick; Marepally, Srujan; Patel, Apurva; Jackson, Tanise; Sarkar, Shubhashish; O’Connell, Malaney; Reddy, Rakesh C; Chellappan, Srikumar; Singh, Pomila; Singh, Mandip

    2015-01-01

    The role of side populations (SP) or cancer stem-like cells (CSC) in promoting the resistance phenotype presents a viable anticancer target. Human-derived H1650 SP cells over-express annexin A2 (AnxA2) and SOX2, and are resistant to conventional cytotoxic chemotherapeutics. AnxA2 and SOX2 bind to proto-oncogenes, c-Myc and c-Src, and AnxA2 forms a functional heterotetramer with S100A10 to promote tumor motility. However, the combined role of AnxA2, S100A10 and SOX2 in promoting the resistant phenotype of SP cells has not been investigated. In the current studies, we examined for the first time a possible role of AnxA2 in regulating SA100A10 and SOX2 in promoting a resistant phenotype of lung tumors derived from H1650 SP cells. The resistance of H1650 SP cells to chemotherapy compared to H1650 MP cells was investigated by cell viability studies. A short hairpin RNA targeting AnxA2 (shAnxA2) was formulated in a liposomal (cationic ligand-guided, CLG) carrier and characterized for size, charge and entrapment and loading efficiencies; CLG carrier uptake by H1650 SP cells was demonstrated by fluorescence microscopy, and knockdown of AnxA2 confirmed by qRT-PCR and Western blot. Targeting of xenograft and orthotopic lung tumors was demonstrated with fluorescent (DiR) CLG carriers in mice. The therapeutic efficacy of CLG-AnxA2, compared to that of placebo, was investigated after 2 weeks of treatment in terms of tumor weights and tumor burden in vivo. Compared to mixed population cells, H1650 SP cells showed exponential resistance to docetaxel (15-fold), cisplatin (13-fold), 5-fluorouracil (31-fold), camptothecin (7-fold), and gemcitabine (16-fold). CLG carriers were nanoparticulate (199 nm) with a slight positive charge (21.82 mV); CLG-shAnx2 was of similar size (217 nm) with decreased charge (12.11 mV), and entrapment and loading efficiencies of 97% and 6.13% respectively. Fluorescence microscopy showed high uptake of CLG-shAnxA2 in H1650 SP cells after 2 h resulting in a

  15. Treatment of brain metastasis from lung cancer.

    PubMed

    Kawabe, Takuya; Phi, Ji Hoon; Yamamoto, Masaaki; Kim, Dong Gyu; Barfod, Bierta E; Urakawa, Yoichi

    2012-01-01

    Brain metastasis from lung cancer occupies a significant portion of all brain metastases. About 15-20% of patients with non-small cell lung cancer (NSCLC) develop brain metastasis during the course of the disease. The prognosis of brain metastasis is poor with median survival of less than 1 year. Whole-brain radiation therapy (WBRT) is widely used for the treatment of brain metastasis. WBRT can also be used as adjuvant treatment along with surgery and stereotactic radiosurgery (SRS).Surgery provides a rapid relief of mass effects and may be the best choice for a large single metastasis. SRS confers local control rates comparable to those for surgery with minimal toxicities and versatility that makes it applicable to multiple lesions, deep-seated lesions, and to pati