Dissertations / Theses on the topic 'Lung carcinomas'
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Xinarianos, George. "Genetic alterations in non-small cell lung carcinomas." Thesis, University of Liverpool, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.343688.
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Kim, Young. "The Effects of Tarsh Overexpression on Lung Carcinomas." VCU Scholars Compass, 2013. http://scholarscompass.vcu.edu/etd/498.
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Lung cancer arises from epithelial cells that line the air passages of the lungs. It is the second most common malignancy in the United States; trends suggest that over 228,000 new patients will be diagnosed with lung cancer in 2013. Due to the fact that lung cancer is highly aggressive, it has proven difficult to control. The 5-year survival rate has been shown to be only 15.9%, despite the advances made in terms of diagnosis and treatment. Therefore, we are faced with the problem of finding more effective methods that allow for an earlier diagnosis and the improved treatment of lung cancer. This study attempts to address these issues by investigating Tarsh, a novel molecule that is involved in the regulation of cellular senescence. Previous studies have shown that Tarsh is expressed in normal lung cells, but is significantly downregulated in lung tumors. These studies also determined that Tarsh is likely dependent upon the expression of p53, a tumor suppressor gene. The current study investigated these results, in addition to the biological effects of ectopically increasing Tarsh and/or knocking down p53 expression in two lung cancer cell lines: A549 and H1299 cell lines. It was determined that increasing the expression of Tarsh decreased the rate of proliferation in both cell lines. Additionally, it was shown that the knockdown of p53 increased proliferation in A549 cells. In regards to the migration rate of these cell lines, the overexpression of Tarsh decreased migration in A549 cells, but had no effect on H1299 cells. However, the role of p53 in migration is still unclear. The results of this study suggest that the knockdown of p53 decreases cell migration in A549 cells. This contradicts the fact that H1299 cells do not express p53, yet was found to have the highest migration rate. It is evident that a further investigation is needed to make more concrete conclusions. Nevertheless, the suppressive features of Tarsh on cell proliferation, and possibly migration, make it a promising target of research for lung cancer therapy.
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Merikallio, H. (Heta). "Claudins and epitheliomesenchymal transition in lung carcinomas and chronic obstructive pulmonary disease." Doctoral thesis, Oulun yliopisto, 2013. http://urn.fi/urn:isbn:9789526202471.
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Abstract Lung cancers and chronic obstructive pulmonary disease (COPD) are the most common smoking-related lung diseases and both have high mortality rate. Tight junctions (TJ) are apical junctions between epithelial cells that regulate the permeability of epithelium and form the tight junction along with occludin. Dysfunction of the TJ and dysregulation of TJ proteins leads to a loss of cell-cell adhesion and a loss of cohesion as well as epitheliomesenchymal transition. These increase invasion of lung carcinomas and possibly predispose to the exacerbations in COPD. Therefore, the aim of this thesis was to study expression and regulation of claudins in different lung carcinomas and COPD. Carcinomas expressed claudins 1, 2, 3, 4, 5 and 7 in different variations. Claudin 5 expression was weak in all carcinoma types. Strong claudin 1, 4 and 7 expression was associated with better survival in squamous cell carcinoma and adenocarcinoma. Claudin 3 expression was associated with COPD in large airways. Claudins 3 and 4 was found to be stronger in small airways of smokers and COPD patients than in non-smokers. Transcription factor snail had prognostic value in lung carcinomas. Negative snail expression was associated with longer life expectancy in lung carcinoma patients. Negative snail expression was associated with up-regulated claudin 5 and 7 expression, while strong expression was associated with low claudin 1 and 3 expression. Transcription factors slug and twist were inversely associated with claudins 3 and 4 in small and large airways. Slug expression was higher in non-smokers than in COPD patients and smokers. Transcription factor knockdown increased claudin expression in normal bronchial cell line. Except for claudin 2 and 7, which were decreased. Adenocarcinoma-like cell line was not affected by snail knockdown and in squamous cell carcinoma-like cell line claudin 3, 4 and 7 expression was increased. Transcription factor snail knockdown inhibited invasion of cell lines. Twist knockdown increased transepithelial resistance in normal bronchial cell line indicating higher barrier function in cell layerTiivistelmä Keuhkosyöpä ja keuhkoahtaumatauti ovat yleisiä tupakoinnin aiheuttamia keuhkosairauksia, joissa on korkea kuolleisuus. Tupakointi aiheuttaa muutoksia keuhkojen epiteelisoluissa ja solujen välisissä liitoksissa. Tiivisliitokset solujen välillä säätelevät epiteelin rakennetta ja läpäisevyyttä. Klaudiinit ovat proteiineja, jotka muodostavat tiivisliitoksen yhdessä okkludiinin kanssa. Tiivisliitos proteiinien toimintahäiriöt voivat johtaa solujen välisten liitosten katoamiseen ja epiteelin hajoamiseen sekä epiteelisolujen muuntumiseen mesenkymaalisten solujan kaltaisiksi. Nämä seikat lisäävät invaasiota keuhkosyövissä ja saattavat altistaa pahenemisvaiheisiin keuhkoahtaumataudissa. Väitöskirjassa tutkittiin klaudiinien ilmentymistä ja säätelyä keuhkosyövässä ja keuhkoahtaumataudissa. Klaudiinien1, 2, 3, 4, 5 ja 7 esiintyminen keuhkosyövän histologisissa alatyypeissä vaihteli. Klaudiinien 1, 4 ja 7 voimakas ilmentyminen voitiin yhdistää pidempään elinikään potilailla, joilla oli levyepiteeli- tai adenokarsinooma. Klaudiini 3:n ilmentyminen liittyi keuhkoahtaumatautiin suurissa hengitysteissä. Klaudiinien 3 ja 4 voimakas ilmeneminen pienissä ilmateissä oli yleisempää keuhkoahtaumatautipotilailla ja tupakoitsijoilla kuin tupakoimattomilla henkilöillä. Transkriptiotekijä snailin puuttuminen keuhkosyövässä liittyi potilaiden pidempään elinaikaan. Klaudiinien 5 ja 7 ilmeneminen oli voimakkaampaa, kun snailin määrä oli vähäinen. Klaudiinien 1 ja 3 ilmeneminen väheni snail:in ollessa voimakas keuhkosyövässä. Traskriptiotekijöiden (slug ja twist) ilmeneminen liittyi käänteisesti klaudiinien ilmentymiseen pienissä ja suurissa ilmateissä. Slugin ilmeneminen oli voimakkaampaa tupakoimattomilla henkilöillä kuin tupakoivilla tai keuhkoahtaumatautia sairastavilla. Transkriptiotekijöiden snail, slug ja twist toiminnan estäminen lisäsi klaudiinien määrää normaaleissa keuhkon epiteelisoluissa. Poikkeuksen muodostivat klaudiinit 2 ja 7, joiden määrä väheni kun snail:in toiminta oli estetty. Adenokarsinooma-soluissa snailin estolla ei ollut vaikutusta, ja levyepiteelisyövän soluissa klaudiinien 3, 4 ja 7 määrä kasvoi. Snail myös vähensi solujen invaasiota. Transkriptiotekijä twistin toiminnan esto normaaleissa keuhkoepiteelisoluissa nosti solumaton läpi kulkevan sähkön resistenssiä, mikä on osoitus tiiviistä solujen välisistä liitoksista
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Vieira, Thibault. "Caractérisation des carcinomes sarcomatoïdes primitifs pulmonaires." Thesis, Paris 6, 2016. http://www.theses.fr/2016PA066552/document.
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Les carcinomes sarcomatoïdes sont un sous type rare de cancer bronchique non à petites cellules (CBNPC). Leur pronostic semble plus défavorable que celui des autres sous-types de CBNPC. Notre équipe travaille sur le démembrement moléculaire de ces tumeurs. Dans ce travail, nous démontrons que les carcinomes sarcomatoïdes sont chimiorésistants aux sels de platine à partir d'étude in vivo et in vitro (cultures primaires) comparativement aux autres sous-types de CBNPC. Nous démontrons que tumeurs partagent les caractéristiques phénotypiques des CBNPC tant d'un point de vue immunohistochimique que moléculaire, confortant la classification OMS. Il est possible que ces tumeurs dérivent de cellules souches de CBNPC ou utilisent un processus de transition épithélio-mésenchymateuses. Les spécificités de cette transition restent à déterminer. De plus, ces tumeurs présentent de très nombreuses altérations moléculaires permettant d'envisager de nouvelles pistes de traitements ciblés notamment les anti-MET. Enfin, nous montrons l'implication du système immunitaire avec une infiltration importante de lymphocytes T CD8+, de macrophages CD163+ et une forte expression de PD-L1 ce qui ouvre de nouvelles perspectives de recherche et de traitements innovantsSarcomatoid carcinomas are a rare subtype of non-small cell lung cancer (NSCLC). Prognostic seems less favourable than other subtypes of NSCLC. Our team works to determine molecular characteristics of these tumors. In this work, we demonstrated that sarcomatoid carcinomas are chemoresistant to platinum based regimen in vitro and in vivo (primary cell lines) compared to other NSCLC. We demonstrated that this tumors share immunohistchemical, moleculary similarities with NSCLC validating the WHO classification. It is possible that these tumors came from cancer stem cell or underwent an epithelial-mesenchymal transition. Specificities of this transition remained undefined. Moreover these tumors presented a lot of molecular alterations allowing to investigate targeted therapies such as MET inhibitors. At last, we shows the implication of the immune system, the strong infiltration of TCD8+ lymphcoytes CD163+ macrophages and the expression of PD-L1, allowing to hope new perspective of research, innovative treatment
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Blat, Irene Catherine. "Functional miRNA regulation of metastatic genes promotes tumor cell dissemination in non-small cell and small cell lung carcinomas." Thesis, Massachusetts Institute of Technology, 2013. http://hdl.handle.net/1721.1/80982.
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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, 2013.Cataloged from PDF version of thesis. Vita.
Includes bibliographical references.
Tumor progression, from initiation to advanced metastatic disease, requires the orchestration of a diverse group of cell-intrinsic and extrinsic factors. This multifactorial disease is promoted by an accumulation of genetic and epigenetic changes that confer selective advantage to cells and enable unrestrained proliferation, survival, motility, and self-renewal. While much emphasis over the last 35 years has been dedicated to understanding the regulators of tumor initiation, the number of cancer-related deaths worldwide continues to rise, of which the majority are attributed to metastasis. The lengthy progression to metastasis requires invasion out of the primary tumor site and into the bloodstream, survival in and exit from circulation, and colonization and expansion in a foreign environment. Developmental pathways such as the Transforming Growth Factor [beta] (TGF[beta]) signaling network are frequently dysregulated during metastatic progression due to the similarities between early embryogenesis and tumor progression. Furthermore, the TGF[beta] pathway highlights how cell-intrinsic and extrinsic signals help coordinate the complex interactions required between tumor cells, as well as those of the tumor microenvironment to achieve metastasis. Facilitating alterations to pathways such as TGF[beta] and many others are modulators of gene expression that can target multiple nodes of the signaling cascade instead of requiring genetic alterations to single genes. Moreover, in the last decade, emphasis on the role of noncoding RNAs in post-transcriptional modifications has revealed their important contribution in the regulation of developmental programs across metazoan species. More recently, the role of alterations in expression of small noncoding RNAs, microRNAs (miRNAs) has emerged as a significant contributor to disease states, including each stage of tumor progression from initiation to metastatic colonization. miRNAs hold great promise not only as biomarkers but also as potential therapeutics. For these reasons, we have characterized the role of two important examples of miRNA families - the miRNA-200 family and the miRNA-1 7~92 cluster - that regulate early stages of tumor initiation in addition to later steps of cell migration, invasion, survival, and colonization. Examination of their contribution to tumor progression in relevant in vitro and in vivo cellular contexts using genetic tools reveals they are functional contributors to tumor cell dissemination. Furthermore, modulation of their expression in the appropriate tumor microenvironments elucidates a network of targets underlying the molecular mechanisms of metastasis.
by Irene Catherine Blat.
Ph.D.
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Gonterman, Ryan M. "Parathyroid hormone-related protein gene expression and function relationship with oncogenic pathways in the skin and squamous cell carcinomas of the lung /." [Bloomington, Ind.] : Indiana University, 2008. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3324517.
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Thesis (Ph.D.)--Indiana University, Dept. of Medical Sciences, 2008.Title from PDF t.p. (viewed on May 13, 2009). Source: Dissertation Abstracts International, Volume: 69-08, Section: B, page: 4693. Adviser: John G. Foley.
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Zschaeck, Sebastian, Monique Simon, Steffen Löck, Esther G. C. Troost, Kristin Stützer, Patrick Wohlfahrt, Steffen Appold, et al. "PRONTOX – proton therapy to reduce acute normal tissue toxicity in locally advanced non-small-cell lung carcinomas (NSCLC): study protocol for a randomised controlled trial." BioMed Central, 2016. https://tud.qucosa.de/id/qucosa%3A30184.
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Background
Primary radiochemotherapy with photons is the standard treatment for locally advanced-stage non-small cell lung cancer (NSCLC) patients. Acute radiation-induced side effects such as oesophagitis and radiation pneumonitis limit patients’ quality of life, and the latter can be potentially life-threatening. Due to its distinct physical characteristics, proton therapy enables better sparing of normal tissues, which is supposed to translate into a reduction of radiation-induced side effects.
Methods/design
This is a single-centre, prospective, randomised controlled, phase II clinical trial to compare photon to proton radiotherapy up to 66 Gy (RBE) with concomitant standard chemotherapy in patients with locally advanced-stage NSCLC. Patients will be allocated in a 1:1 ratio to photon or proton therapy, and treatment will be delivered slightly accelerated with six fractions of 2 Gy (RBE) per week.
Discussion
The overall aim of the study is to show a decrease of early and intermediate radiation-induced toxicity using proton therapy. For the primary endpoint of the study we postulate a decrease of radiation-induced side effects (oesophagitis and pneumonitis grade II or higher) from 39 to 12%. Secondary endpoints are locoregional and distant failure, overall survival and late side effects.
Trial registration
Registered at ClinicalTrials.gov with Identifier NCT02731001 on 1 April 2016.
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Zschaeck, Sebastian, Monique Simon, Steffen Löck, Esther G. C. Troost, Kristin Stützer, Patrick Wohlfahrt, Steffen Appold, et al. "PRONTOX – proton therapy to reduce acute normal tissue toxicity in locally advanced non-small-cell lung carcinomas (NSCLC): study protocol for a randomised controlled trial." Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2017. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-219714.
Full textAbstract:
Background
Primary radiochemotherapy with photons is the standard treatment for locally advanced-stage non-small cell lung cancer (NSCLC) patients. Acute radiation-induced side effects such as oesophagitis and radiation pneumonitis limit patients’ quality of life, and the latter can be potentially life-threatening. Due to its distinct physical characteristics, proton therapy enables better sparing of normal tissues, which is supposed to translate into a reduction of radiation-induced side effects.
Methods/design
This is a single-centre, prospective, randomised controlled, phase II clinical trial to compare photon to proton radiotherapy up to 66 Gy (RBE) with concomitant standard chemotherapy in patients with locally advanced-stage NSCLC. Patients will be allocated in a 1:1 ratio to photon or proton therapy, and treatment will be delivered slightly accelerated with six fractions of 2 Gy (RBE) per week.
Discussion
The overall aim of the study is to show a decrease of early and intermediate radiation-induced toxicity using proton therapy. For the primary endpoint of the study we postulate a decrease of radiation-induced side effects (oesophagitis and pneumonitis grade II or higher) from 39 to 12%. Secondary endpoints are locoregional and distant failure, overall survival and late side effects.
Trial registration
Registered at ClinicalTrials.gov with Identifier NCT02731001 on 1 April 2016.
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Rangel, Maristela Peres. "Relevância dos proteoglicanos como biomarcadores prognósticos e preditivos em carcinomas não-pequenas células e seu impacto na carcinogênese pulmonar." Universidade de São Paulo, 2016. http://www.teses.usp.br/teses/disponiveis/5/5144/tde-01032017-140343/.
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Introdução. Os glicosaminoglicanos e os proteoglicanos são moléculas abundantes na matriz extracelular. Vários estudos têm demonstrado que uma produção ou degradação aberrante dessas moléculas tem influência no comportamento do câncer de mama, cólon e pâncreas. Outras proteínas como o solCD44 e a cofilina-1 também tem demonstrado influência direta na progressão dos tumores. Desta forma, a análise da expressão destas moléculas em tecidos e fluidos corporais tem despertado grande interesse como rastreador de indivíduos de alto risco e marcador diagnóstico e/ou prognóstico da doença. Objetivos. Conhecer o impacto do ácido hialurônico e dos proteoglicanos (biglicam, glipicam, perlecam, sindecam e versicam) na carcinogênese bem como seu impacto na sobrevida dos pacientes; verificar se a concentração de solCD44 e cofilina-1 presente no escarro de pacientes com câncer de pulmão permite rastreá-los entre pacientes com doença pulmonar obstrutiva crônica e voluntários saudáveis. Resultados. Uma associação significativa direta foi encontrada entre os tumores com alto percentual de expressão de AH e de microvasos no estroma tumoral. As concentrações de heparam e condroitim sulfato nas amostras tumorais foram mais elevadas quando comparadas às amostras não tumorais. Com exceção do sindecam, todos os outros proteoglicanos apresentaram uma expressão gênica significativamente menor nos tecidos tumorais e biglicam e versicam apresentaram associações com as características clinico patológicas. A expressão proteica de biglicam, perlecam e versicam foi significativamente maior no tecido normal do que nas áreas de estroma tumoral e de células tumorais. Pela análise de regressão de COX controlada para idade, tipo histológico e expressão gênica de biglicam, sindecam e glipicam obtiveram alta taxa de sobrevida os pacientes do sexo feminino com elevada expressão gênica de perlecam e menor risco de óbito em estadio T1, ausência de metástases nodais e expressão gênica de versicam. A Maristela Peres Rangel Tese de doutorado - USP concentração de cofilina demonstrou-se mais elevada no escarro de pacientes com câncer de pulmão quando comparado ao escarro de pacientes de alto risco e de voluntários saudáveis. A concentração de solCD44 também demonstrou-se mais elevada no escarro de pacientes com câncer de pulmão quando comparado ao escarro de pacientes de alto risco e de voluntários saudáveis. Através da curva ROC, a cofilina-1 presente no escarro foi capaz de distinguir os pacientes de alto risco dos pacientes com câncer de pulmão com área abaixo da curva de 0.69 e com um ponto de corte de 802.5 pg/mL a curva apresentou 60% de sensibilidade e 54% de especificidade. O solCD44 presente no escarro também foi capaz de distinguir os pacientes de alto risco dos pacientes com câncer de pulmão através da curva ROC com área abaixo da curva de 0.67 e com um ponto de corte de 65.8 pg/mL a curva apresentou 50% de sensibilidade e 84% de especificidade. Conclusão. A expressão do ácido hialurônico demonstrou ter correlação no processo de crescimento tumoral através da angiogênese. A análise biomolecular apontou a diminuição dos proteoglicanos no tecido tumoral e, portanto, estes podem ser potenciais biomarcadores prognósticos de câncer de pulmão. As análises feitas em escarro demonstraram que a elevada expressão proteica de solCD44 e da cofilina-1 no escarro nos pacientes com câncer de pulmão mostram-se como promissores alvos de detecção do CPIntroduction. The relationship between the extracellular matrix (ECM) components and cancer cells have an important role on cancer development and progression. Between the most important molecules present on the ECM are the glycosaminoglycans and their respective proteoglycans. Studies have reported that they have different behaviours when in the presence of malignant tissues and influence the development of breast, pancreas and colon cancers. Likewise, proteins as solCD44 and cofilin-1 also have shown direct influence in tumor progression. Regarding that, there is growing interest among scientists in analyzing the expression of these molecules in body fluids as a screening tool of high risk patients and as a diagnostic and prognostic lung cancer biomarker. Objectives. The aims of this study were to recognize the impact of hyaluronan and the proteoglycans (biglycan, glypican, perlecan, syndecan e versican) on lung cancer carcinogenesis as well as its impact on patient\'s survival; verify if the solCD44 e cofilina-1 concentrations in the sputum of lung cancer patients could distinguish them from patients with COPD and healthy volunteers. Results. A direct association was found between tumors expressing high amounts of hyaluronan and CD34 in tumoral stroma. Heparan and chondroitin sulphate concentrations were higher in tumor specimens when compared to normal lung tissue. All proteoglycans, in exception of syndecan, showed a lower expression in tumoral tissue and biglycan and versican showed association with the clinical pathological features. Protein expression of biglycan, perlecan and versican was higher in the normal tissue when compared to stroma and tumoral cells. COX regression controlled by age, histological types and gene expression of biglycan, syndecan e glypican demonstrated that female patients had higher survival rates with high gene expression of perlecan and the patients with T1 stage, lack of linfonode Maristela Peres Rangel Tese de doutorado - USP metastasis and gene expression of versican had lower risk of death. Cofilin-1 concentration was higher in the sputum of lung cancer patients when compared to a high risk group and healthy volunteers. Also, the solCD44 concentration was higher in the sputum of lung cancer patients when compared to a high risk group and healthy volunteers. ROC cruve analysis demonstrated that sputum cofilin-1 was capable to distinguish high risk patients from lung cancer patients with na area under the curve of 0.69 and with a cut off at 802.5 pg/mL the curve presented 60% de sensitivity and 54% specificity. Sputum solCD44 was also capable to distinguish high risk patients from lung cancer patients with na area under the curve of 0.67 and with a cut off at 65.8 pg/mL the curve presented 50% de sensitivity and 84% specificity. Conclusions. Hyaluronan expression showed a correlation with tumoral growth through angiogenesis processes. The biomolecular analysis demonstrated that matrix proteoglycans are potencial lung cancer prognostic biomarkers. Sputum analyses showed that solCD44 and cofilin-1 are potencial molecules in lung cancer detection
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Rangel, Maristela Peres. "Relevância clínica da concentração do ácido hialurônico no escarro e em espécimes tumorais de pacientes portadores de carcinomas de pulmão." Universidade de São Paulo, 2012. http://www.teses.usp.br/teses/disponiveis/5/5160/tde-25102012-162649/.
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Introdução. O ácido hialurônico é um glicosaminoglicano não sulfatado presente na matriz extracelular. Vários estudos têm demonstrado que uma produção ou degradação aberrante dessa molécula tem influência no comportamento do câncer de mama, próstata, bexiga e pulmão. Desta forma, a dosagem do ácido hialurônico em tecidos e fluidos corporais como sangue, urina e escarro tem despertado grande interesse como rastreador de indivíduos de alto risco e marcador diagnóstico e/ou prognóstico da doença estabelecida. Objetivos. Verificar se há diferenças nos níveis de ácido hialurônico entre espécimes tumorais e não tumorais de câncer de pulmão, bem como seu impacto na sobrevida dos pacientes; verificar se diferenças encontradas nos tecidos estão também presentes no escarro; verificar se a dosagem do ácido hialurônico no escarro permite rastrear pacientes com câncer de pulmão entre pacientes com doença pulmonar obstrutiva crônica e voluntários saudáveis. Resultados. Houve uma elevação significativa nos níveis de ácido hialurônico nos espécimes tumorais em relação aos espécimes não tumorais, mesmo quando histologicamente categorizados. Não houve associação entre as concentrações do ácido hialurônico com características clínicas dos pacientes, porém houve impacto na sobrevida dos pacientes: pacientes com tumores contendo ácido hialurônico > 364,36 g/g apresentaram menor sobrevida global que pacientes cujos tumores evidenciaram ácido hialurônico < 364,36 ug/g. Demonstramos que pacientes com câncer de pulmão apresentam elevações altamente significativas da produção de ácido hialurônico no escarro independente das características clínicas dos pacientes, porém dependente do tipo histológico. Valores de ácido hialurônico >11,13ng/mg no escarro tem sensibilidade de 87% para rastreamento de pacientes com câncer de pulmão e voluntários saudáveis. Nesse grupo valores > 31,44ng/mg tem especificidade de 100% e sensibilidade de 51%. Houve exclusão com sensibilidade de 33% e especificidade de 100% de pacientes com doença pulmonar obstrutiva crônica em relação aos pacientes com câncer de pulmão para valores > 48,36ng/mg. Conclusão. Diferentes níveis de ácido hialurônico forma observados nos tumores e tecidos normais com impacto na sobrevida dos pacientes, tornando a dosagem do ácido hialurônico como promissor marcador prognóstico no câncer de pulmão. Diferenças observadas nos tecidos foram também constatadas no escarro, despontando a dosagem do ácido hialurônico como promissora no rastreamento de indivíduos com risco para câncer de pulmãoIntroduction. Hyaluronan is an extracellular matrix non-sulfated glycosaminoglycan. Some have reported that its abnormal production and degradation can influence the behaviour of different types of tumours like breast, prostate, bladder and lung cancer. Therefore, hyaluronan quantitative analysis in tissues and body fluids like blood, urine and sputum has shown promise on the high risk patients screening and as diagnostic/prognostic marker of some diseases. Objectives. Verify if there are differences in the levels of hyaluronan in tumoral and non-tumoral lung cancer specimens, as well as its impact on the patients survival; verify if sputum samples present the same differences; verify the role of hyaluronan quantitative analysis in the screening of lung cancer patients between patients with chronic obstructive pulmonary disease and healthy volunteers. Results. Lung cancer tumoral specimens showed higher levels of hyaluronan when compared to non-tumoral specimens even when the specimens were histologically categorized. There was no correlation between hyaluronan levels and the patients clinical features, however, an impact in the patients survival was observed: patients with tumoral hyaluronan levels > 364,36 g/g had a lower survival rate than patients with < 364,36 ug/g. We have shown that lung cancer patients show an elevated production of hyaluronan in the sputum. This characteristic was independent of the clinical features but dependent of the histologic type. The hyaluronan quantitative analysis for the screening of lung cancer patients between healthy volunteers showed a sensitivity of 87% for hyaluronan levels >11,13ng/mg in the sputum. In this group levels > 31,44ng/mg showed 100% specificity and 51% sensibility. On a second group (lung cancer patients vs chronic obstructive pulmonary disease patients) levels of sputum hyaluronan > 48,36ng/mg showed 100% specificity to exclude chronic obstructive pulmonary disease patients from lung cancer patients. The sensibility for this cut-off point was 33%. Conclusion. Hyaluronan quantitative analysis in the tissues is a promising lung cancer prognostic marker considering the differences between hyaluronan levels on tumoral and nontumoral tissues. Not only this, but, the differences observed in the tissues were observed in the sputum as well. Hence, the hyaluronan quantitative analysis is a promising strategy in the screening of high risk individuals that might develop lung cancer
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Rêgo, Juliana Florinda de Mendonça. "Análise e comparação da expressão imunoistoquímica de marcadores moleculares (ERCC1, Bcl-2, Lin28a e Ki67) potencialmente preditores de resposta à quimioterapia em carcinomas neuroendócrinos extra-pulmonares e carcinoma de pequenas células de pulmão." Universidade de São Paulo, 2016. http://www.teses.usp.br/teses/disponiveis/5/5155/tde-06022017-155301/.
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INTRODUÇÃO: O carcinoma de pulmão de pequenas células (CPPC) e o carcinoma neuroendócrino (CNE) extra-pulmonar apresentam características histopatológicas e tratamentos similares, porém os desfechos encontrados nos dois grupos podem ser diferentes. Avaliamos a expressão de alguns biomarcadores e a associação destes com taxa de resposta (TR) à quimioterapia baseada em platina e sobrevida global (SG) nos dois grupos. METODOS: Realizamos estudo retrospectivo de pacientes com CPPC e CNE extra-pulmonares tratados com quimioterapia baseada em platina. Todas as amostras tumorais foram revisadas pelo mesmo patologista (R.S.S.M.) e analisadas quanto a expressão imunoistoquímica de Ki-67, ERCC1, Bcl-2 e Lin28a, a qual foi determinada através do H-escore (calculado multiplicando o produto da intensidade da coloração - 0 a 3 - com a porcentagem de células positivas - 0 a 100 -, podendo variar de 0 a 300 - positivo quando >= 200). Os biomarcadores foram analisados tanto como variáveis contínuas quanto categóricas e a TR foi determinada por RECIST 1.1. A associação entre a expressão de cada biomarcador e a TR foi avaliada através do teste de qui-quadrado ou teste exato de Fisher para variáveis categóricas e regressão logística simples para variáveis contínuas. Sobrevida global foi estimada por Kaplan-Meier e as curvas foram comparadas por log-rank. O modelo de regressão de cox foi utilizado para avaliar associação entre SG e a expressão de biomarcadores como variável contínua. RESULTADOS: Entre Julho de 2006 e Julho de 2014, 142 pacientes foram identificados: N=82 (57,7%) com CPPC e N=60 (42,3%) com CNE extra-pulmonar. As características clínicas eram semelhantes em ambos os grupos. Mediana de ki67 foi de 60% (7-100) no CPPC e de 50% (20-95%) no segundo grupo (p=0,858). Com uma mediana de 5 ciclos por paciente (N=123 elegíveis para análise de TR), a TR foi de 86,8% no CPPC, enquanto nos com CNE extra-pulmonar, foi de 44,6% (p < 0.001). A mediana de SG (N=132 elegíveis para análise da SG) foi similar entre os grupos (10,3 meses em CPPC e 11,1 meses em CNE extra-pulmonar; p=0,069). Não houve diferença no padrão de expressão do ERCC1 (p=0,277) e do Lin28a (p=0,051) entre os grupos. Bcl2 foi expresso em 38 pacientes (46,3%) com CPPC e em 17 pacientes (28,3%) com CNE extra-pulmonar (p=0,030). Apenas no grupo com CNE extra-pulmonar, a alta expressão do Bcl2 foi associada com pior prognóstico (8,0 meses vs 14,7 meses; p=0,025). A expressão dos demais marcadores em CNE extra-pulmonar e dos quatro em CPPC não apresentou influência sobre a SG, não havendo também associação entre estes e a taxa de resposta à quimioterapia. Dentre os pacientes com CNE extra-pulmonar, não houve diferença na SG ou na TR entre os pacientes com carcinoma bem diferenciado (N=13;) e com carcinoma pouco diferenciado (N=47). CONCLUSÃO: Apesar do CPPC e do CNE extra-pulmonar serem tratados de forma semelhante, nesta coorte a taxa de resposta entre os grupos foi significativamente diferente. Quando comparado com CPPC, os pacientes com CNE extra-pulmonar apresentam uma menor responsividade à quimioterapia baseada em platina, mas com tendência a maior SG. Dentre os CNE extra-pulmonares, a alta expressão de Bcl-2 foi associada a pior prognóstico. Os demais biomarcadores não apresentaram papel preditor de resposta ou prognósticoINTRODUCTION: Small cell lung cancer (SCLC) and high-grade extrapulmonary neuroendocrine carcinomas (EPNEC) share similar histopathological features and treatment, but outcomes may differ. We evaluated the expression of biomarkers and their association with response rate (RR) to platin-based chemotherapy and overall survival (OS) in these entities. METHODS: We conducted a retrospective analysis of patients with advanced EPNEC and SCLC treated with platinum-based chemotherapy. A single pathologist (R.S.S.M.) revised all samples. Paraffin-embedded tumor samples were tested for Ki-67, ERCC1, Bcl-2 and Lin28a expression by immunohistochemistry (IHC). Final IHC score (H-score) was calculated multiplying the intensity of staining by grading (0-300, with >= 200 considered positive). Biomarkers were analyzed as both categorical and continuous variables. RR was determined by RECIST 1.1. Associations between each biomarkers expression and RR were assessed using Chi-square or Fisher\'s exact test for categorical variables and univariate logistic regression for continuous variables. OS was estimated by the Kaplan-Meier method and curves were compared by log-rank. Cox regression analysis was used to evaluate any association between biomarkers expression (continuous variables) and OS. RESULTS: From July 2006 to July 2014, 142 patients were identified: N=82 (57,7%) with SCLC and N=60 (42,3%) with EPNEC. Baseline clinical characteristics were similar. Median Ki67 was 60% (7-100) among SCLC patients and 50% (20-95%) in EPNEC (p=0,858). With a median of 5 cycles per patient in both groups (N=123 evaluable patients), the RR was significantly higher in the SCLC group (86,8% vs 44.6%; p < 0.001). Median OS (N=132 evaluable patients) was similar between the groups (10.3 months in SCLC and 11.1 months in EPNEC; p=0,069). In the EPNEC group, there wasn\'t any difference in OS or RR between the patients with welldifferentiated (N=13) and poorly differentiated carcinoma (N=47). ERCC1 (p=0.277) and Lin28a (p=0.051) were similarly expressed between the groups. Bcl2 was expressed in 38 SCLC patients (46.3%) and in 17 EPNEC patients (28.3%; p=0.030). Only in the EPNEC group, Bcl2 high expression was associated with worse survival (8.0 months vs 14.7 months; p = 0.025). RR to chemotherapy was not influenced by the expression of the ERCC1, Lin28a, Bcl-2, Ki-67 in either EPNEC or SCLC groups. CONCLUSION: Even though SCLC and EPNEC are treated similarly, in this cohort, the rate response differed significantly. When compared with SCLC, patients with EPNEC apparently had tumors less responsive to platin-based chemotherapy, but tended to live longer. In EPNEC treated with platin, high expression of Bcl2 was associated with poor prognosis. We could not identify additional predictive or prognostic biomarkers
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Piton, Nicolas. "Optimisation de la prise en charge diagnostique, pronostique et théranostique des carcinomes broncho-pulmonaires humains : des techniques d’imagerie in vivo à la biologie moléculaire. Ligation -dependent RT-PCR : a new specific and low-cost technique to detect ALK, ROS and RET rearrangements in lung adenocarcinoma A new assay for detection of theranostic gene translocations and MET exon 14 skipping in thoracic oncology. One-year perspective routine LD-RT-PCR in 413 newly diagnosed lung tumors STK11 mutations are associated with lower PDL1 expression in lung adenocarcinoma BRAF V600E mutation is not always present as expected ! A case report of lung and thyroid carcinomas A novel method for in vivo imaging of solitary lung nodules using navigational bronchoscopy and confocal laser microendoscopy." Thesis, Normandie, 2019. http://www.theses.fr/2019NORMR119.
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Le carcinome pulmonaire est une affection grave et fréquente dont la prise en charge a été bouleversée ces dernières années, tant sur le plan diagnostique que pronostique ou « théranostique » avec l’avènement des « thérapies ciblées ». Ces dernières permettent une nette amélioration de la survie et du confort des patients éligibles, mais ne sont pas sans compliquer le travail médical, depuis le diagnostic de la maladie jusqu’au suivi régulier du patient, sans oublier le choix des traitements ou les problèmes techniques posés par la multiplication arborescente des altérations moléculaires à rechercher à partir d’un tissu tumoral souvent peu abondant dans ce contexte particulier de l’oncologie thoracique. Ce travail de thèse collige 5 travaux de recherche selon deux angles d’approche : les marqueurs moléculaires pronostiques et « théranostiques » du cancer pulmonaire, et les procédures de diagnostic in vivo de cette pathologie. Le premier axe comporte 4 articles. Les deux premiers concernent l’évaluation d’une nouvelle technique moléculaire, la LD-RT-PCR, dans la détection des translocation géniques du cancer pulmonaire : la première étude est une étude de faisabilité, la deuxième est un travail de validation. Le troisième article explore l’association entre la présence d’une mutation STK11 dans les carcinomes pulmonaires et l’expression de PDL1. Enfin, le quatrième article est une étude de cas illustrant l’importance de l’approche morphologique du cancer pulmonaire. Le second axe est représenté par un travail comparant une technique d’imagerie in vivo par voie endoscopique utilisant la micro-endoscopie confocale par laser avec l’approche microscopique conventionnelleLung cancer is a serious and frequent condition for which the management strategies have been dramatically modified in recent years, from a diagnostic, prognostic and “theranostic” perspective, most notably with the introduction of “targeted therapies”. The latter have demonstrated dramatic improvement in both quality of life and survival rates of eligible patients, yet consequently highlight new complications in diagnosis, treatment options or technical considerations which can be attributed to the growing number of molecular alterations to be detected from limited tissue samples frequently encountered in thoracic oncology. This work combines 5 different research papers from 2 different angles: prognostic and “theranostic” molecular markers of lung cancer, as well as in vivo diagnostic procedures of lung cancer. The first angle encompasses 4 articles. The first two evaluate a new molecular technique, LD-RT-PCR, to detect gene translocation in lung cancer. The third article explores the association between STK11 mutations in lung cancer and the expression of PDL1. Finally, the fourth article is a case report illustrating the importance of a morphological approach to lung cancer. The second angle compares in vivo imaging techniques by endoscopy using confocal laser microendoscopy alongside a conventional microscopic approach
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Terlizzi, Michela. "Role of the inflammasome in lung cancer Inflammasome is involved in lung carcinogenesis." Doctoral thesis, Universita degli studi di Salerno, 2017. http://hdl.handle.net/10556/2410.
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2014 - 2015Lung cancer is recognized as one of the most devastating tumor worldwide due to the low rate survival over 5 years from the time of diagnosis. Inflammation has been widely recognized as the seventh hallmark of cancer as it facilitates the establishment/development and progression of lung cancer. In this context, recent evidence highlighted the role of the inflammasome during carcinogenesis. However, little is still known. The inflammasome is a multiprotein complex that leads to caspase-1 activation which role in lung cancer is still under investigated. In this context, the aim of my PhD project was to understand the role of the inflammasome in lung cancer in a mouse model of carcinogen-induced lung cancer and in human non-small cell lung cancer (NSCLC). We found that both caspase-1-dependent, the canonical pathway, and caspase-8/caspase-11-dependent, the non-canonical pathway, inflammasome were involved during lung cancer establishment and progression in both mice and humans. Our data showed that the pharmacological inhibition of both caspase-1 and caspase-8 significantly reduced lung tumor outgrowth associated to lower pro-inflammatory response and to a reduced lung recruitment of immunesuppressive cells and that caspase-8 was upstream caspase-1 activation during lung carcinogenesis. Furthermore, we showed that caspase-11 was the primary/main orchestrator of the inflammasome-dependent lung cancer progression and that the enzyme could be upstream of caspase-1 to induce the amplification of the occurring inflammatory process associated to lung cancer development. Finally, we identified a novel mechanism by which lung tumor-associated macrophages could favor lung tumorigenesis via the activation of caspase-11-dependent inflammasome and the consequent release of the pro-tumorigenic IL-1α. [edited by author]
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Moraes, Adriel dos Santos 1976. "Administração de nanotubos de carbono "multiwalled" in vivo ativa citotoxicidade tumor-específica de linfócitos T CD8+." [s.n.], 2012. http://repositorio.unicamp.br/jspui/handle/REPOSIP/259942.
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Orientador: Vitor BaranauskasDissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Engenharia Elétrica e de Computação
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Resumo: A administração "in vivo" de nanotubos de carbono "multi-walled" (MWCNT's), mesmo sem serem funcionalizados, estimula o aparecimento de uma reposta imune em camundongos normais. Nesse trabalho nós fornecemos evidências de que essas nanopartículas de carbono também estimulam a resposta imune em camundongos portadores de tumor. Os MWCNT's (100 ?g) diluídos em PBS contendo 0,1 % de Pluronic 127 foram inoculados sistemicamente em camundongos portando tumores cujos tamanhos atingiram 5 milímetros (mm) e a resposta imune foi avaliada nos linfonodos desses animais. Observamos que os tumores de animais que receberam as nanopartículas não cresceram como os tumores dos animais não tratados. A discreta inibição do crescimento do carcinoma pulmonar de Lewis (LLC) foi acompanhada pela ativação de linfócitos T CD8+ tanto em número quanto em função. A ativação da função citotóxica dos linfócitos T CD8+ pode ser explicada pelo aumento da expressão de citocinas pertencentes à família da IL-12, principalmente IL-27, que é descrita como a citocina envolvida na estimulação da citotoxicidade de linfócitos T CD8+. Nossos dados demonstraram que nanotubos de carbono "multi-walled", mesmo sem funcionalização estimula resposta imunológica antitumoral
Abstract: The "in vivo" administration of multi walled carbon nanotubes (MWCNT's) even without functionalization stimulates the immune response of naïve mice. Here we provide evidence that these carbon nanoparticles also stimulated the immune response of tumor-bearing mice. The MWCNT's (100 ?g) diluted in PBS with 0,1% of Pluronic 127 were inoculated systemically in mice with tumor that reached 5 mm and the immune response was evaluated in the lymph nodes. We observed that the tumors that received the nanoparticles did not grow as the untreated tumor. The discrete inhibition of the growth of the Lewis Lung Carcinoma (3LL) was accompanied by activation of CD8 T lymphocytes both in number and in function. The activation of the cytotoxic function of CD8 T lymphocytes may be explained by the increase of expression of cytokines belongs to the IL-12 family, mainly the IL-27, which is described as a cytokines involved in the stimulation of CD8 T lymphocytes cytotoxic function. Our data demonstrated that MWCNT even without functionalization stimulated the antitumor immune response
Mestrado
Eletrônica, Microeletrônica e Optoeletrônica
Mestre em Engenharia Elétrica
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Yan, Dejun. "THE EFFECT OF CURCUMIN ON LEWIS LUNG CARCINOMA." Bowling Green State University / OhioLINK, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=bgsu1308588440.
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Ritchie, Andrew John. "Endocrinology, oncogene expression and outcome in carcinoma of the lung." Thesis, Queen's University Belfast, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.357457.
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Nahreini, Piruz. "Regulation of Lewis lung carcinoma cell growth by prostaglandins." Virtual Press, 1985. http://liblink.bsu.edu/uhtbin/catkey/424559.
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A cloned metastatic variant of a murine tumor cell line, Lewis lung carcinoma (LLC(C3), was synchronized by double exposure to thymidine (5 x 10-4 M) at G1/S boundary. The effects of Prostaglandin (PG)E1, PGE2, PG synthetase inhibitors, and an analog of cAMP (dbut-cANP) on the life cycle of synchronized LLC(C3) cells were examined. When added to cells in G1 phase, PGE1 and dbut-cAMP enhanced 3H-thymidine uptake during S phase. Both of these agents suppressed S phase when they were added to cells entering S phase. The addition of PGE2 to LLC(C3) cells in G1 phase had no effect on S phase of the synchronized LLC(C3) cells. Prostaglandin E2 suppressed S phase when it was added at the beginning of S phase. A low concentration of PGE2 was more suppressive to S phase than was a high concentration. Indomethacin, an irreversible PG synthetase inhibitor, and piroxicam, a reversible PG synthetase inhibitor, suppressed S phase of synchronized LLC(C3) cells. These results suggest that prostaglandins can regulate the cell cycle of LLC(C3) cells through modulation of cAMP levels.
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Wright-Perkins, Shirley. "Characteristics and interrelationships of cell lines derived from an undifferentiated bronchial carcinoma." Thesis, University of Liverpool, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.317361.
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McLean, John S. "The modulation of the phenotype of human-non-small cell lung cancer." Thesis, University of Glasgow, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.236727.
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Nordman, Ina IC Clinical School St Vincent's Hospital Faculty of Medicine UNSW. "Surrogate endpoints of survival in metastatic carcinoma." Publisher:University of New South Wales. Clinical School - St Vincent's Hospital, 2008. http://handle.unsw.edu.au/1959.4/42791.
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In most randomised controlled trials (RCTs), a large number of patients need to be followed over many years, for the clinical benefit of the drug to be accurately quantified (1). Using an early proxy, or a surrogate endpoint, in place of the direct endpoint of overall survival (OS) could theoretically shorten the duration of RCTs and minimise the exposure of patients to ineffective or toxic treatments (2, 3). This thesis examined the relationship between surrogate endpoints and OS in metastatic colorectal cancer (CRC), advanced non-small cell lung cancer (NSCLC) and metastatic breast cancer (MBC). A review of the literature identified 144 RCTs in metastatic CRC, 189 in advanced NSCLC and 133 in MBC. The publications were generally of poor quality with incomplete reporting on many key variables, making comparisons between studies difficult. The introduction of the CONSORT statement was associated with improvements in the quality of reporting. For CRC (337 arms), NSCLC (429 arms) and MBC (290 arms) there were strong relationships between OS and progression free survival (PFS), time to progression (TTP), disease control rate (DCR), response rate (RR) and partial response (PR). Correlation was also demonstrated between OS and complete response (CR) in CRC and duration of response (DOR) in MBC. However, while strong relationships were found, the proportion of variance explained by the models was small. Prediction bands constructed to determine the surrogate threshold effect size indicated that large improvements in the surrogate endpoints were needed to predict overall survival gains. PFS and TTP showed the most promise as surrogates. The gain in PFS and TTP required to predict a significant gain in overall survival was between 1.2 and 7.0 months and 1.8 and 7.7 months respectively, depending on trial size and tumour type. DCR was a better potential predictor of OS than RR. The results of this study could be used to design future clinical trials with particular reference to the selection of surrogate endpoint and trial size.
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Sirzén, Florin. "Molecular aspects of cellular radiosensitivity in small cell lung carcinoma /." Stockholm, 1998. http://diss.kib.ki.se/1998/19981204sirz/.
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Wheeler, Elizabeth H. "Natural killer cell activity in mice bearing Lewis lung carcinoma." Virtual Press, 1985. http://liblink.bsu.edu/uhtbin/catkey/416656.
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Natural killer (NK) cells are important in limiting tumor dissemination. The NK activity in C57B1/6 mice bearing Lewis lung carcinoma (LLC) was monitored during tumor development. During the initial period of tumor growth, NK activity was enhanced. As tumor growth progressed, NK activity became suppressed. Depletion of macrophages from the spleen cells of tumor-bearing mice restored the NK cytotoxic response. Plasma prostaglandin E2 (PGE2) concentrations were measured by a radioimmunoassay and found to become elevated during the course of tumor growth. To determine whether the suppressed NK activity might have been a result of the elevated levels of PGE2, mice were treated with a prostaglandin synthesis inhibitor, indomethacin. Indomethacin treatment prevented the rise in plasma PGE2 concentrations and the suppression in NK activity. These results support the hypothesis that the suppression of NK activity in tumor bearers is mediated by PGE2 which might be produced by the host's suppressor macro-phages.
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Culak, Renata A. "Characterisation of selected sialoglycoproteins isolated from human lung carcinoma cells." Thesis, University of East London, 2001. http://roar.uel.ac.uk/3572/.
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Carbohydrate moieties on the cell surface play an important role in cellular recognition. Increased sialylation of cell surface glycoproteins has been reported in malignant tumours and has been correlated with the invasive and metastatic potential of the cells. The aim of this work was to investigate the expression of cell membrane glycoproteins on four lung cancer cell lines and to identify potential changes in their sialylation employing the tools of proteomics and functional genomics. Three highly metastatic cell lines: PC 14- human lung adenocarcinoma, PLC- primary liver carcinoma and T24- human bladder carcinoma were chosen for the preliminary studies. Methods optimized on the above cell lines were then employed to isolate and purify membrane proteins from four human lung cancer cell lines, including two adenocarcinoma cell lines (PC 14 and SK-Lu 1), squamous cell carcinoma (SK-Mes 1) and small cell carcinoma (NCI-H82). Two methods were used to assess the state of glycosylation of the proteins. Firstly the samples were treated with endoglycosidases (Peptide N-glycosidase and O-glycanase) and changes in electrophoretic mobility between enzyme-treated and non-treated controls were used to reveal removal of glycans. In the second method proteins were transferred from gels by Western blotting and the blots probed with lectins. Four biotinylated lectins were used: concanavalin A (Con A), wheat germ agglutinin (WGA), Sambucus nigra agglutinin (SNA) and Maackia amurensis (MAA II). Significant differences in the binding patterns for the lectins were observed. Binding of MAA II and SNA confirmed the presence of a2,3-linked and cc2,6-linked sialic acids respectively. Binding of Con A suggested extensive expression of N-linked glycans with a high content of mannose. It was suspected that results obtained by Western blotting were affected by shedding of sialic acid residues during protein purification. Hence, in a second approach to the study of glycoprotein sialylation the expression of two sialyltransferase genes at the mRNA level was investigated. The enzyme mainly responsible for the addition of a2,6-linked sialic acids is p-galactoside cc2,6- sialyltransferase (ST6Gal I) and mRNA for this enzyme was detected in all four lung tumour cell lines examined. This was not the case with the p-galactoside a2,3- sialyltransferase III (ST3Gal III). A very weak response was detected in PC 14 cell line only, but not in the other three cell lines. It was concluded that oc2,3 sialylation detected by binding of MAA II lectin was due to the action of other a2,3-sialyltransferases. A final part of the work concentrated on a specific glycoprotein, mainly CD44. CD44 is a major hyaluronan-binding protein and is implicated in cell-cell adhesion, cell-matrix interaction and metastasis. The presence of the CD44 antigen on cell membranes and expression of the CD44 gene were nvestigated. The CD44 gene contains over 20 exons and 12 of them are alternatively spliced. It was observed that different histologic types of lung cancer expressed different forms of the CD44 antigen. Adenocarcinoma of lymphoblastoid origin (PC 14 cell line) showed the expression of several isoforms including the standard form CD44S, epithelial form CD44R and variant form CD44v. Small cell carcinoma (NCI-H82 cell line) did not express CD44 at either the protein or mRNA level. Two other cell lines examined (SK-Lu 1 adenocarcinoma and SK-Mes 1 squamous cell carcinoma) expressed only the CD44S form. In summary the results obtained suggest that the expression of the CD44 molecule on lung cancer cell lines differs between histological types of tumour and could be related to the metastatic potential of the cells.
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Hemström, Anna Therése Helén. "Apoptosis, cellular division or mitotic catastrophe? : effects of kinase inhibition and DNa damage in lung cancer cells /." Stockholm, 2006. http://diss.kib.ki.se/2007/978-91-7357-031-2/.
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Ekedahl, Jessica. "Apoptotic signaling in lung carcinoma cells with focus on mechanisms of radioresistance /." Stockholm, 2003. http://diss.kib.ki.se/2003/91-7349-502-6/.
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林華杰 and Wah-kit Lam. "A clinical and epidemiological study of carcinoma of lung in HongKong." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 1985. http://hub.hku.hk/bib/B31981264.
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Prochazka, Michaela. "The risk of second primary lung carcinoma in breast cancer patients /." Stockholm, 2006. http://diss.kib.ki.se/2006/91-7140-649-2/.
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Chu, Ka-wan Kevin. "High-throughput molecular characterization of human non-small cell lung carcinoma /." View the Table of Contents & Abstract, 2007. http://sunzi.lib.hku.hk/hkuto/record/B38165107.
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Chu, Ka-wan Kevin, and 朱嘉運. "High-throughput molecular characterization of human non-small cell lung carcinoma." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2007. http://hub.hku.hk/bib/B4501288X.
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Lorch, Gwendolen. "Mechanisms of Receptor-Mediated Hypercalcemia in Human Lung Squamous Cell Carcinoma." The Ohio State University, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=osu1242659291.
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Lam, Wah-kit. "A clinical and epidemiological study of carcinoma of lung in HongKong." [Hong Kong : University of Hong Kong], 1985. http://sunzi.lib.hku.hk/hkuto/record.jsp?B12318061.
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Chatterjee, Saradiya. "Role of TLR7 in non-small cell lung carcinona (NSCLC)." Paris 6, 2013. http://www.theses.fr/2013PA066063.
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Le cancer du poumon cause de plus d’un million de décès par an, et le progonstique est très somber, avec un taux de survie à 5 ans de l’ordre de 8 à 12%. La stimulation des TLRs par des ligands agonistes naturels comme les PAMPs et les DAMPs résulte en l’activation d’une cascade de signalisation conduisant à l’expression de molecules proinflammatoires. Nous avons montré que la stimulation de lignées cellulaires de tumeur pulmonaire par des agonistes de TLR7 induit une survie cellulaire et une résistance à la mort induite par chimiothérapie in vitro. Nous avons étudié in vivo les effets d’injections d’agonistes de TLR7 sur la croissance tumorale et la résistance à la chimiothérapie dans des souris NOD/SCID et C57BL/6. L’injection de loxoribine, ou de CL264 a un effet pro-tumoral sur la croissance des cellules A549 et CL264, respectivement, et induit une chimioresistance dans des souris NOD/SCID. Le blocage de TLR7 réverse l’effet pro-tumoral de l’agoniste. Par ailleurs, l’injection de faible dose de CL264 a un effet anti-tumoral sur les cellules LL/2, alors que l’injection d’une forte concentration de l’agonsite a un effet pro-tumoral. Nous avons également démontré qu’une forte expression de TLR7 par les cellules tumorales de patients NSCLC est de mauvais pronostique sur la survie globale des patients. Ces résultats démontrent le rôle pro- tumoral de TLR7 et son implication potentielle dans le phénomène de chimiorésistance. Ainsi l’utilisation d’agonistes de TLR7 comme adjuvant de vaccination antitumorale devrait prendre en compte le niveau d’expression de TLR7 sur les cellules tumorales des patientsLung cancer accounts for over 1 million deaths per year with a 5-year survival of 8-12%. Stimulation of TLRs by the natural ligands like the PAMPs and DAMPs results in a proinflammatory signaling cascade. We have shown that stimulation of lung cancer cell lines with TLR7 agonist lead to tumor cell survival and chemoresistance in vitro. We studied the effect of TLR7 agonists on A549 and LL/2 cells injected in NOD/SCID and C57BL/6 mice either treated or not with cisplatin. Loxoribine has a pro-tumoral effect on A549 cells and induces chemoresistance in NOD/SCID mice. Blockade of TLR7 with IRS661 reversed the pro-tumoral effect of TLR7 agonist on A549 cells. CL264 was also found to have a pro-tumoral effect on LL/2 cells and induced chemoresistance in NOD/SCID mice. On the other hand CL264 at lower concentration induces an anti-tumoral effect on LL/2 cells while at a higher concentration demonstrated a pro-tumoral effect in C57BL/6 mice. We also demonstrated an overall bad prognostic value for higher expression of TLR7 by tumoral cells among NSCLC patients treated and not treated with neoadjuvant chemotherapy. These results suggest a pro- tumoral role and induction of chemoresistance by TLR7 in NSCLC patients. Use of TLR7 agonist as therapeutic option is recommended based on the TLR7 expression level for individual NSCLC patients. TLR7 antagonist holds promise for treatment of NSCLC in future
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Aguirre, Egaña Itziar de. "LKB1/ AMPK / TSC2 signaling pathway alterations in non-small-cell-lung-carcinoma." Doctoral thesis, Universitat Autònoma de Barcelona, 2014. http://hdl.handle.net/10803/284322.
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El gen supresor tumoral LKB1/STK11b, codifica una serina/treonina quinasa. Las mutaciones de línea germinal en LKB1 están asociadas al síndrome de Peutz-Jeghers (PJS), trastorno dominante autosómico caracterizado por el crecimiento de pólipos en el tracto gastrointestinal, y depósitos de melanina mucocutánea, aumentando el riesgo de ciertos cánceres, incluido el de pulmón. El locus de PJS se encuentra situado en el cromosoma 19p13.3 y el gen responsable fue identificado como LKB1. Las mutaciones del gen LKB1 también están asociadas a los adenocarcinomas de pulmón, ocurren aproximadamente en un tercio de los tumores primarios y en la mitad de las líneas celulares de adenocarcinoma de pulmón, implicando a LKB1 en la patogénesis del cáncer de pulmón. Estudios recientes sugieren que la vía de señalización de LKB1 juega un papel en la protección de las células frente a la apoptosis, en respuesta a niveles de energía o nutrientes bajos, lográndose en parte a través de la supresión de la actividad de mTOR. Hay evidencias en la bibliografía que demuestran que LKB1 activa al complejo heterotrimerico AMPK, formado por tres subunidades, una catalítica (α) y dos reguladoras (β y γ). AMPK es un sensor de energía celular que contribuye a regular el balance energético y la ingesta calórica en la célula. Posteriormente, AMPK fosforila a TSC2. El heterodímero TSC1-TSC2 actúa para inhibir la actividad de mTOR, que es esencial para el control del crecimiento celular y la proliferación. Así, LKB1 funciona como un regulador negativo de mTOR. Está demostrado que LKB1 también regula 11 de las 12 quinasas de la subfamilia de quinasas AMPK in vitro, sugiriendo que una de las funciones del gen supresor LKB1 podría ser la regulación de la vía de señalización de AMPK. Por tanto, LKB1 podría ser un blanco potencial para el tratamiento de cáncer y trastornos metabólicos.
Nuestros principales objetivos fueron: ▪ Determinar la frecuencia de alteraciones genéticas y epigenéticas en la vía de señalización LKB1/AMPK/TSC2 en CPCNP, en un panel de 23 líneas celulares (4 líneas celulares epiteliales normales bronquiales inmortalizadas con SV40 y 19 líneas celulares de CPCNP). ▪ Estudiar el estado de metilación de 4 quinasas de la subfamilia de quinasas AMPK: BRSK1, BRSK2, MARK1 MARK4 en 23 líneas celulares. ▪ Examinar la vía LKB1/BRSK2. ▪Analizar el estado de metilación de BRSK2 en 58 FFIP de pacientes con CPCNP. ▪ Determinar el impacto de la pérdida de LKB1 en líneas celulares de CPCNP.
Las principales conclusiones fueron: ▪ Las mutaciones de LKB1 no se limitan a los adenocarcinomas, también ocurren en otro subtipo de CPCNP, los carcinomas de células grandes. No se encontró metilación en el promotor de LKB1 en ninguna de las líneas celulares de cáncer pulmón analizadas en este estudio. ▪ No se detectaron mutaciones ni ningún grado de metilación en los distintos componentes estudiados de AMPK y TSC en las 23 líneas celulares analizadas. ▪ De la subfamilia de quinasas de AMPK analizadas, el estado de metilación del promotor BRSK2 representa el de mayor porcentaje: ~ 26% de las líneas celulares y 25,8% del grupo de 58 FFIP de pacientes con CPCNP. ▪ El estado de metilación de BRSK2 se correlaciona significativamente con cuatro parámetros clinicopatológicos: estadio tumoral (P = 0, 025), histología (P = 0, 001), tamaño tumoral (P = 0, 073) y nódulos afectados (P = 0, 04), sugiriendo que el estado de metilación del promotor BRSK2 podría utilizarse como un nuevo biomarcador en la progresión del cáncer de pulmón. ▪ La interrupción de la vía LKB1/BRSK2 podría ser un importante mecanismo molecular, durante el desarrollo del cáncer de pulmón.LKB1, also known as STK11b, is a serine/threonine kinase that functions as a suppressor of tumor growth. Germ line mutations in LKB1 are associated with the Peutz-Jeghers syndrome (PJS), an autosomal dominant disorder characterized by benign hemartomas of the gastrointestinal tract and mucocutaneous melanin deposits and an increased risk of certain cancers, including lung. The main PJS locus has been mapped to chromosome 19p13.3, and the gene responsible was identified as LKB1. Mutations in LKB1 gene are also associated with sporadic lung adenocarcinomas and occurs in approximately one-third of primary tumors and half of lung adenocarcinoma cells lines, implicating LKB1 in the pathogenesis of lung cancer. Recent evidence suggests that LKB1 signaling plays a role in protecting cells from apoptosis in response to energy or nutrient deprivation, which is achieved in part through the suppression of mTOR activity. Evidence from the literature supports a protein kinase cascade model in which LKB1 phosphorylates AMPK. AMPK is a heterotrimeric complex comprising a catalytic subunit (α) and two regulatory subunits (β and γ) that act as an intracellular energy sensor maintaining the energy balance within the cell. AMPK subsequently phosphorylates TSC2. Together the TSC1-TSC2 heterodimer acts to suppress the activity of mTOR, which is essential for the control of cell growth and proliferation. Thus, LKB1 functions as a negative regulator of mTOR. Additionally, LKB1 has been shown to regulate 11 of the 12 AMPK family members in vitro, suggesting that one of the tumour suppressor functions of LKB1 may be regulation of AMPK signaling. Therefore, LKB1 could be a potential target for treatment of both cancer and metabolic disorders. In this work we sought to study the signal transduction LKB1/AMPK/TSC2 pathway alterations that contribute to the pathogenesis NSCLC. Our major objectives were: ▪To determine the frequency of genetic and epigenetic alterations in the signal traduction LKB1/AMPK/TSC2 pathway in NSCLC in a panel of 23 cell lines (4 normal bronchial epithelial cell lines immortalized with SV40 and 19 NSCLC cell lines). ▪ To study some components of AMPK-related kinase family that could be activated downstream of LKB1, in particular we analyzed the methylation status of: BRSK1, BRSK2, MARK1, MARK4 in our panel of 23 cell lines. ▪ To examine LKB1/BRSK2 signaling.▪ To make a clinical validation of BRSK2 methylation status, in 58 FFPE of patients with NSCLC. ▪ To determinate the impact of LKB1 depletion on NSCLC cell lines. The major conclusions of this work were: ▪ LKB1 mutations are not confined to adenocarcinomas, they also occur in other NSCLC subtype such as large cell carcinomas. But we found no evidence of LKB1 methylation in any NSCLC cell lines used in this study. ▪ There are not sequence alterations or/and promoter methylation of AMPK and TSC components studied in our 23 panel cell lines. ▪ Of the four AMPK related kinases -BRSK1, BRSK2, MARK1 and MARK4- studied, BRSK2 represents the highest percentage of methylation; ~26 % of NSCLC cell lines and 25.8% in the 58 NSCLC samples. ▪ BRSK2 methylation is significantly correlated with four clinicopatological parameters: tumor stage (P=0,025), histology (P=0,001), tumor size (P=0,073) and nodules affected (P=0,04), suggesting that methylation of BRSK2 could provide a novel biomarker for disease progression in lung cancer. ▪ The disruption of LKB1/BRSK2 signaling could be important in the carcinogenesis of lung, as a molecular mechanism for the development of lung cancer.
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Fenwick, Jill. "A quantitative multiparametric cytochemical analysis of small cell carcinoma of the lung." Thesis, Liverpool John Moores University, 1997. http://researchonline.ljmu.ac.uk/4901/.
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Casadevall, Aguilar David. "Heterogeneity of biomarker expression in non-small cell lung cancer." Doctoral thesis, Universitat Autònoma de Barcelona, 2017. http://hdl.handle.net/10803/457975.
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L’èxit de de la medicina de precisió en oncologia depèn, en gran mesura, d’una adequada selecció dels pacients que rebran teràpies dirigides contra dianes específiques del seu tumor. Per poder seleccionar els pacients, és indispensable disposar de biomarcadors amb valor predictiu que informin les decisions terapèutiques.
MET i PD-L1 són dos receptors de membrana rellevants en la biologia del carcinoma pulmonar no microcític (CPNM). MET és un oncogen i l’activació de la seva via es troba relacionada amb múltiples processos pro-tumorals com són la proliferació i la motilitat cel·lulars, així com la invasió d’estructures veïnes. PD-L1 és una molècula clau en la resposta immunitàries, i la seva sobre-expressió en els tumors està relacionada amb la capacitat de les cèl·lules tumorals d’evitar el seu reconeixement i destrucció per part del sistema immunitari. Actualment, existeixen teràpies específiques dirigides contra aquestes molècules. L’estratègia més emprada per seleccionar els pacients que se’n poden beneficiar és la determinació de l’expressió d’ambdues molècules en teixit tumoral. Tanmateix, el valor de MET i de PD-L1 com a biomarcadors predictius i el mètode pel qual s’han de determinar és subjecte de debat.
Estudis recents han detectat un alt grau d’heterogeneïtat genòmica en mostres tumorals en CPNM. Aquesta heterogeneïtat podria afectar de forma rellevant la classificació de pacients basada en l’expressió de biomarcadors. A més, aquest fet seria especialment rellevant en el cas del CPNM, ja que l’estudi de biomarcadors es fa generalment en mostres petites de teixit, provinents de biòpsies o citologies obtingudes mitjançant tècniques mínimament invasives. L’objectiu principal dels treballs presentats en aquesta tesi és estudiar l’heterogeneïtat de l’expressió de MET i PD-L1 en mostres de CPNM.
Amb aquesta finalitat, hem analitzat mostres tumorals procedents de pacients tractats quirúrgicament de CPNM a l’Hospital del Mar. De cada tumor, hem seleccionat múltiples àrees geogràficament separades, les quals hem analitzat de forma independent. En l’estudi en que hem avaluat MET hem seleccionat quatre àrees per cada pacient, mentre que en l’estudi de PD-L1 n’hem seleccionat dues. En cada àrea tumoral, hem mesurat l’expressió de MET i de PD-L1 mitjançant mètodes d’immunohistoquímica i d’hibridació in situ fluorescent (FISH). Finalment, hem comparat l’expressió de MET i de PD-L1 entre diferents àrees tumorals.
En el cas de MET, hem trobat discordances entre diferents àrees tumorals en un 20-40% per immunohistoquímica i en un 25-50% per FISH. En el cas de PD-L1, aquesta discordança ha estat major si es valora només l’expressió en limfòcits infiltrants de tumor (17-27%) que si es valora en cèl·lules tumorals (10-19%). A més, un 36% dels casos amb amplificació del gen que codifica PD-L1 determinada per FISH presenten aquesta amplificació només en una de les dues àrees analitzades.
En conjunt, els nostres resultats suggereixen que l’expressió d’ambdós biomarcadors és heterogènia, tant si es mesura mitjançant immunohistoqumímica com mitjançant FISH. Aquesta heterogeneïtat pot tenir un impacte potencial en la classificació de tumors basada en l’expressió de biomarcadors i per tant, pot suposar una dificultat afegida a l’hora de desenvolupar teràpies dirigides per pacients amb CPNM.The success of precision medicine in oncology is dependent to a large extent on an adequate selection of patients who will receive targeted therapies aimed at specific molecular traits of their tumor. In order to be able conduct such patient selection, predictive biomarkers that can inform therapeutic decisions are essential. MET and PD-L1 are two relevant membrane receptors for non-small cell lung cancer (NSCLC) biology. MET is an oncogene the activation of which is involved in multiple pro-tumorigenic processes such as cell proliferation, motility and invasion. PD-L1 is a key molecule that acts during the immune response, and its overexpression in tumors is thought to mediate the ability of tumor cells to avoid immune cell recognition and destruction. Currently, there are specific therapies directed against these molecules. The most commonly used strategy to select the patients that will benefit from such drugs is the analysis of the expression of both molecules in tumor tissue. However, the value of MET and PD-L1 as predictive biomarkers and the method by which it should be determined is a subject of debate. Recent studies have detected a high degree of genomic heterogeneity in NSCLC tumor samples. This heterogeneity could significantly affect biomarker-based patient classification especially in the case of NSCLC, since biomarker studies are usually performed in small biopsies or cytology samples obtained through minimally invasive techniques. The main objective of the work presented in this thesis is to study the heterogeneity of the expression of MET and PD-L1 in NSCLC samples. For this purpose, we have analyzed tumor samples from NSCLC patients that had undergone surgical treatment at Hospital del Mar. Of each tumor, we have selected multiple geographically separate areas, which we analyzed independently. In the study evaluating MET, we selected four tumor areas per patient, while in the study evaluating PD-L1 we selected two areas. In each tumor area, we measured the expression MET and PD-L1 using immunohistochemical and fluorescence in situ hybridization methods (FISH). Finally, we compared the expression of MET and PD-L1 in different tumor areas. Regarding MET, we have found discordances between different tumor areas in 20-40% of cases using immunohistochemistry and in 25-50% of cases using FISH. Regarding PD-L1, this discrepancy was greater if we evaluated PD-L1 expression in tumor infiltrating lymphocytes (17-27%) than if we did so only in tumor cells (10-19%). Moreover, 36% of the cases with amplification of the gene coding for PD-L1 determined by FISH presented gene amplification only in one of the two areas analyzed. Overall, our results suggest that the expression of both biomarkers is heterogeneous, whether measured by immunohistochemistry or by FISH. This heterogeneity can have a potential impact on the classification of tumors based on the expression of biomarkers and, therefore, could represent a hurdle for the development of targeted therapies for NSCLC patients.
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Fernández, Araujo Esther. "Carcinoma broncogénico. supervivencia quirúrgica de pIIIpN2." Doctoral thesis, Universitat Autònoma de Barcelona, 2018. http://hdl.handle.net/10803/664284.
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El tratamiento y manejo del estadio IIIA-N2 del cáncer de pulmón (CPNCP) continua siendo controvertido y objeto de debate en congresos tanto de oncología torácica como de cirugía torácica. La principal razón es debido a que el estadio IIIA-N2 CPNCP comprende un grupo heterogéneo de pacientes que incluye diferentes subgrupos. La mayoría de los estudios muestran una supervivencia de estos pacientes a 5 años de entre el 6-35% después de la cirugía. Sin embargo, es sabido que los pacientes con N2 insospechado tienen una mejor supervivencia. El objetivo de este estudio es analizar la supervivencia de los pacientes afectos de CPNCP con N2 hallado intraoperatoriamente. Analizamos la supervivencia en los siguientes supuestos: afectación de una única estación pN2 frente a múltiples estaciones pN2, supervivencia en pacientes pN1 + pN2, supervivencia según la histología de carcinoma escamoso o adenocarcinoma, asociación entre tamaño tumoral (T) y pN2 y supervivencia en pacientes con carcinoma broncogénico en LLSS y afectación de ganglios linfáticos en el mediastino superior. Se trata de un estudio retrospectivo que incluye dos series. La serie 1 incluye pacientes del 1995 al 2001 y la serie 2 del 2008 al 2011. Se han analizado un total de 121 pacientes de las serie 1 pN2 insospechado y 31 de la serie 2. La supervivencia a 5 años ha sido del 18% y 40% respectivamente y ésta constituye la mayor diferencia entre ambas series. En las dos series hemos hallado una mejor supervivencia en pacientes con un única estación pN2 afecta frente a múltiples así como una mejor supervivencia en pacientes con tumores localizados en el lóbulo superior derecho y afectación ganglionar 4R y una tendencia a mejor supervivencia en pacientes con tumores en lóbulo superior izquierdo y afectación ganglionar estación 5-6. No hemos podido demostrar una mejor supervivencia en pacientes con “skip metástasis”. No hemos podido demostrar asociación entre la histología y el tamaño tumoral con la afectación pN2. Podemos concluir que la tasa de pN2 insospechados hallados en la serie actual es mucho menor gracias a la introducción de nuevas técnicas de estadificación como son la PET-TAC y el EBUS. La resección pulmonar en un paciente pN2 hallado intraoperatoriamente no debe negarse más si se puede tratar con una lobectomía.Management of Stage IIIA-N2 non-small-cell lung cancer (NSCLS) that represents locally advanced disease with the involvement of ipsilateral mediastinal lymph nodes remains highly controversial and is hotly debated during every major conference of thoracic oncology and surgery. The main reason is that Stage IIIA-N2 NSCLS is not a homogeneous disease entity and comprises quite distinct subgroups. The most studies shows a 5-year survival between 6-35% after surgery alone. Although unexpected N2 seems to have a better overall survival. The aim of this study is to analyze the survival of patients NSCLS without clinical suspicion of mediastinal lymph node involvement who underwent complete resection and whose lung cancer were finally proven to be pathologic N2 (pN2). We analyze the survival in this subjects: one pN2 station vs multiple pN2 station, survival in patients with pN1 + pN2, survival in squamous cell and adenocarcinoma in patients pN2, T factor and pN2 and upper lobes lung cancer and upper mediastinal lymph node pN2. This is a retrospective study that includes two series. Serie 1 from 1995 to 2001 and series 2 from 2008 to 2011. A total of 121 patients unexpected pN2 in series 1 and 31 patients unexpected pN2 in series 2 were analyzed. 5-year survival rates were 18% and 40% respectively and that’s the first bigger difference between two series. In both series we met a better survival in only one pN2 station versus multiples pN2 stations and a also a better survival in right upper lobe lung cancer and 4R lymph node involvement and a trend to a better survival in upper left lobe lung cancer and 5-6 involvement. We cannot demonstrate a better survival in patients with “skip metastasis”. We also cannot identify a correlation between histology and T status with pN2. In conclusion the rate of unsuspected pN2 in recent patients is low thanks to the introduction of new technology for staging lung cancer as PET-TAC and EBUS. Therefore, resection of properly staged unexpected pN2 NSCLC is reasonable and should not be avoided especially if a lobectomy is feasible.
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Näpänkangas, U. (Ulla). "Apoptosis in non-small cell carcinoma and preinvasive bronchial lesions of the lung." Doctoral thesis, Oulun yliopisto, 1999. http://urn.fi/urn:isbn:9514253302.
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Abstract
Failure to maintain an appropriate balance between cell death and proliferation is partly due to derangements in the regulation of apoptosis. In this work, apoptosis and the expression of apoptosis regulating proteins were studied by 3' - end labeling of fragmented apoptotic DNA (TUNEL) and immunohistochemistry in a set of 147 tissue samples consisting of 44 biopsies of normal and dysplastic bronchial epithelium, and 103 non-small cell lung carcinomas.
The quantity of apoptotic cells and bodies, apoptotic index (AI%), is defined as a percentage of apoptotic cells in the entire tumor cell population. Changes in the apoptotic activity were already seen in the metaplasia-dysplasia-carcinoma sequence of the lung, where the AI% increased gradually until moderate epithelial dysplasia but started to decrease after that. Thus, the AI% for invasive NSCLC (1.20 for squamous cell carcinoma and 1.24 for adenocarcinoma) was slightly lower than in premalignant bronchial epithelium (mean 1.50), but clearly higher than in normal tissue (0.20 for normal bronchial epithelium and 0.24 for lung interstitial cells). 53% of SQCCs and 50% of ACs showed p53 positive nuclei indicative of mutated p53 protein. The immunostaining of bcl-2, bax and mcl-1 revealed diffuse, cytoplasmic staining and was present in most tissues studied. No statistically significant associations between the extent of apoptosis and the expression of p53, bcl-2, bax, or mcl-1 could be found, although . The immunostaining for caspases 3, 6 and 8 was restricted to the tumor areas, reflecting increased apoptotic activity in them. The AI% was significantly higher in NSCLCs in which the single-cell staining pattern for caspase-8 was dominant (P = 0.017), whereas the expression of caspases 3 and 6 had no association with apoptosis. The number of apoptotic cells was significantly higher in NSCLC tumors with a high number of CD3+ and CD8+ T-lymphocytes (P = 0.01) and B-cells (P = 0.05). By multivariate analysis, enhanced apoptosis in NSCLC showed a 1.9-fold risk (95% CI 1.04–3.60; P = 0.04) and p53 positivity a 2.3-fold risk (95% CI 1.30–4.10; P = 0.005) for a shortened survival. Both factors appeared as independent prognostic variables.
Apoptosis is clearly enhanced in premalignant and malignant lung tissue in comparison with normal tissue. Furthermore, the expression of the apoptosis-regulating genes is different in tumor tissue from that in normal tissue, and some of the changes in their expression can be seen even in the premalignant lesions of the bronchial epithelium. The expression of caspases seen only in tumor tissue implies the activation of the apoptotic mechanisms and, thus, the lowered treshold of tumor cells to undergo apoptosis. Even in the advanced stages of the disease, the immune defense is effective and the cytotoxic action of activated CD8+ T-cells clearly involves apoptosis. Based on these results it is concluded that alterations in the apoptotic activity and changes in the expression of apoptosis-regulating genes are associated with malignant transformation and growth in lung tissue.
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Kazawa, Nobutaka. "Small cell lung carcinoma : eight types of extension and spread on computed tomography." Kyoto University, 2007. http://hdl.handle.net/2433/135905.
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Eerola, A. K. (Anna-Kaisa). "Apoptosis and apoptosis regulating proteins and factors in small and large cell lung carcinoma." Doctoral thesis, University of Oulu, 1999. http://urn.fi/urn:isbn:9514254066.
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Abstract
Aptosis denotes a biochemically and morphologically distinct
chain of events leading to self-destruction of cell. It is pivotal
in the maintenance of tissue homeostasis and also plays a role in neoplasm.
In this work, the extent of apoptosis and apoptosis regulating proteins
and factors was studied in a total of 94 patients operated for lung
carcinoma, including 56 small cell lung carcinomas (SCLC) and 38
large cell lung carcinomas (LCLC). The extent of apoptosis was determined
by detecting and counting the relative and absolute numbers of apoptotic
cells and bodies using 3'- end labelling of the apoptotic
DNA. The extent of apoptosis in SCLC was compared with the cell proliferation
activity as determined by Ki-67 immunohistochemistry, with the volume
density of necrosis and with the occurrence of immunohistochemically
detectable p53 and bcl-2 proteins. In order to test the hypothesis
that increased apoptotic activity is connected with neuroendocrine differentiation
and with low differentiation degree in LCLC and that it is regulated
by bcl-2 family proteins, the extent of apoptosis and tumour necrosis
was analysed in relation to the expression of bcl-2 family proteins
bcl-2, mcl-1, bax and bak. Apoptosis, tumour infiltrating lymphocytes
(TILs), and angiogenesis are important factors that contribute to
tumour growth. In the present study immunohistochemical methods
were used to investigate the relationships of these factors and
their role in the prognosis of the patients with LCLC and SCLC.
A remarkably high apoptotic activity was detected in both
SCLC and LCLC. The mean apoptotic index in SCLC was 2.70 % and
in LCLC 2.49 %. Exceptionally high proliferation activity
and high percentage of tumour necrosis was seen in SCLC. 58 % of
SCLC showed more than 40 % of Ki-67 positive nuclei, and
tumour necrosis was seen in 83 % of the cases. P53 protein
accumulation was detected in 38 % and bcl-2 expression
in 50 % of SCLC. The extent of apoptosis in SCLC was inversely
related to tumour necrosis and p53 protein accumulation. In LCLC,
bcl-2 expression was detected in 40 % of the cases. It
was associated with neuroendocrine differentiation and predicted favourable
prognosis of the patients. A high number of T cells and macrophages
with a small number of B cells was detected in both SCLC and LCLC.
The occurrence of intratumoural cytotoxic CD8 cells was associated
with the occurrence of apoptotic bodies in SCLC. The increased number
of intratumoural T cells, CD8-positive cells and macrophages predicted
favourable prognosis of the patients with SCLC. In LCLC, an increased
number of B cells and macrophages, but not T cells, was associated
with better survival.
Iaddition to tumour cells, numerous apoptotic bodies could
also be found within alveolar macrophages within and close to tumour
tissue. In order to test whether such cells could be found in sputum
smears and if their presence could be utilised as a marker of malignancy
in tumour diagnosis, the occurrence of alveolar macrophages with
apoptotic bodies (AMWABs) was analysed in 84 sputum samples and
13 broncho-alveolar lavage (BAL) specimens from patients with and
without lung carcinoma. AMWABs could be found in cytological samples
of the patients with lung carcinoma. In sputum and BAL specimens,
enhanced apoptosis, as measured by an increased number of AMWABs
reflected and was indicative of malignancy. This was also true for
cytological specimens of the patients even when the actual malignant
cells were not found. Therefore the AMWABs served as a marker of
pulmonary malignancy.
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Fujimoto, Masakazu. "Stromal plasma cells expressing immunoglobulin G4 subclass in non-small cell lung cancer." Kyoto University, 2015. http://hdl.handle.net/2433/199170.
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Cosaceanu, Daria. "The use of IGF-IR inhibitors in cancer therapy - a potential approach for sensitizing tumor cells to ionizing radiation /." Stockholm, 2006. http://diss.kib.ki.se/2006/91-7140-911-4/.
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Vincent, Emma Elizabeth. "The role of AKT signalling in insulin resistance and non-small-cell lung carcinoma." Thesis, University of Bristol, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.520254.
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Skrzypek, Klaudia. "Role of microRNAs in non-small cell lung carcinoma : effect of heme oxygenase-1." Thesis, Orléans, 2013. http://www.theses.fr/2013ORLE2001.
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L’hème oxygénase-1 (HO-1), enzyme antioxydante, est capable de prévenir l’initiation tumorale tandis qu’elle promeut la progression de certaines tumeurs et l’angiogenèse. Ce travail a recherché si HO-1 peut moduler les microARNs et régule le développmemnt du carcinome pulmonaire humain non à petites cellules (NSCLC). La surexpression stable de HO-1 dans les cellules du NSCLC NCI-H292 accroit la production globale des miARNs et diminue significativement l’expression des oncomirs et angiomirs, tandis qu’elle augmente les miARNs suppresseurs de tumeurs. Le plus amplement diminué est le miR-378. Dans les cellules surexprimant HO-1 la p53 est aussi augmentée, Ang-1 et MUC5AC diminuées, prolifération migration et potentiel angiogéniques réduits. Les effets de HO-1 sur la prolifération tumorale, la migration et et l’expression de miR-378 sont modulées par CO. Au contraire, la surexpression stable de miR-378 décroit celle de HO-1 et de p53 tandis qu’elle accroît celle de MUC5AC, VEGF, IL-8 et Ang-1 et en conséquence accroit la prolifération, migration la stimulation des cellules endothéliales. L’ajout de HO-1 à des cellules surexprimant miR-378 réverse l’effet de miR-378 sur la prolifération et la migration des cellules cancéreuses. In vivo, les tumeurs surexprimant HO-1 sont de taille réduite, moins vascularisées et oxygénées et moins métastatiques tandis que la surexpression de miR-378 produit les effets inverses. Conformément, chez les patients NSCLC, l’expression de HO-1est réduite dans les métastases lymphatiques par rapport à la tumeur primaire tandis que miR-378 n’est pas modifié de manière significative. En conclusion, les résultats in vitro et in vivo indiquent que l’action coordonnée entre HO-1 et miR-378 module de manière significative la progression et l’angiogenèse du carcinome humain pulmonaire non à petites cellulesHeme oxygenase-1 (HO-1), an antioxidant enzyme can prevent tumor initiation while it has been demonstrated to promote various tumors progression and angiogenesis. Here it was investigated whether HO-1 can modulate microRNAs and regulate human non-small cell lung cancer (NSCLC) development. Stable HO-1 overexpression in NSCLC NCI-H292 cells enhanced global production of miRNAs and significantly diminished expression of oncomirs and angiomirs, whereas upregulated tumor suppressive miRNAs. The most potently downregulated was miR-378. HO-1 overexpressing cells displayed also upregulated p53, downregulated Ang-1 and MUC5AC, reduced proliferation, migration and diminished angiogenic potential. CO was a mediator of HO-1 effects on tumor cells proliferation, migration and miR-378 expression. In contrast, stable miR-378 overexpression decreased HO-1 and p53 while enhanced expression of MUC5AC, VEGF, IL-8 and Ang-1 and consequently increased proliferation, migration and stimulation of endothelial cells. Adenoviral delivery of HO-1 to miR-378 overexpressing cells reversed miR-378 effect on proliferation and migration of cancer cells. In vivo, HO-1 overexpressing tumors were smaller, less vascularized and oxygenated and less metastatic, whereas miR-378 overexpression exerted the opposite effects. Accordingly, in patients with NSCLC, HO-1 expression was lower in metastases to lymph nodes than in primary tumors while miR-378 did not differ significantly. To conclude, in vitro and in vivo data indicate that interplay between HO-1 and miR-378 significantly modulates NSCLC progression and angiogenesis
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Hakami, Fahad Mohammad I. "The role of the homeobox gene HOXD10 in lung and head & neck carcinoma." Thesis, University of Sheffield, 2013. http://etheses.whiterose.ac.uk/5957/.
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Tertil, Magdalena. "Role of thymidine phosphorylase and Nrf2 transcription factor in non-small cell lung carcinoma growth and angiogenesis." Thesis, Orléans, 2013. http://www.theses.fr/2013ORLE2043.
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Le facteur de transcription Nrf2 et les enzymes pro-angiogéniques: hème oxygénase (HO-1) et thymidine phosphorylase (TP) sont considérés comme des cibles potentielles pour les traitements combinatoires anticancéreux contre l’angiogenèse. L'objectif de la présente étude était d'examiner les interactions entre ces protéines dans la modulation du potentiel tumorigène et angiogénique de carcinome pulmonaire non à petites cellules (NSCLC). L’augmentation de l’expression de Nrf2 conduit à la réduction de la prolifération cellulaire et à leur capacité de migration, accompagnée d'une expression accrue de microARN suppresseurs de tumeurs ainsi qu’une réduction de l'oncogène miR-378. Ensuite, le rôle de TP dans les cellules NCI-H292 a été étudiée en la surexprimant in vitro (NCI-TP). Ceci a conduit à une atténuation de potentiel tumorigène comme le montre l'inhibition de la prolifération, de la migration et une amélioration concomitante de potentiel angiogénique qui est plus prononcée en hypoxie et en présence de thymidine. In vivo, les tumeurs NCI-TP ont tendance à croître plus rapidement que les témoins et ils sont également mieux oxygénés. Ces tumeurs ont une expression accrue de cytokines pro-inflammatoires IL-1β et IL-6. Nous avons montré pour la première fois que l’enzyme TP peut être régulé par Nrf2 et HO-1 dans les cellules NSCLC, ce qui peut affecter la croissance tumorale par une modulation de l'angiogenèse et de l'expression de facteurs pro-inflammatoires. La corrélation entre l’expression de TP avec celle de l'IL-1β et d'IL-6 a été également confirmée dans les échantillons cliniques de tumeurs issus de patients atteints de NSCLC. L’ensemble de nos résultats montre la potentialité de cibler l’enzyme TP pour le traitement des cancers NSCLCNrf2, heme oxygenase-1 (HO-1) and thymidine phosphorylase (TP) are considered as potential targets for combinatorial anti-cancer therapies. The aim of the study was to investigate the interplay of these proteins in regulation of growth and angiogenesis in non-small cell lung carcinoma (NSCLC) cells NCI-H292. Stable overexpression of Nrf2 (NCI-Nrf2 cell line) resulted in decreased cell proliferation and migration in vitro, upregulation of tumor suppressor microRNAs and downregulation of oncogenic miR-378 and many MMPs. Silencing of HO-1 in NCI-Nrf2 cells partially reversed the effect on MMP-1, MMP-3 and miR-378. NCI-Nrf2 cells exhibited increased expression of proangiogenic factors IL-8, angiopoietin-1 and TP, which was also upregulated in cell overexpressing HO-1. In both models, the effect was TP reversible by siRNA targeted at HO-1 and possibly mediated by modulation of oxidative status of the cell. Moreover, it was observed that overexpression of TP in vitro attenuated proliferation and migration of NSCLC cells, but increased their angiogenic potential. In vivo, NCI-TP tumors tended to grow faster, were better oxygenated and exhibited increased expression of inflammatory cytokines IL-1β and IL-6. Correlation of TP with IL-1β and IL-6 was also confirmed in clinical samples from NSCLC patients. Overall, our results enforce the notion of targeting TP for treatment of NSCLC
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Ko, Adrien. "Impact de l’autophagie sur la radiosensibilité tumorale." Thesis, Paris 11, 2013. http://www.theses.fr/2013PA11T074.
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Les données existantes sur le rôle de l’autophagie dans la mort cellulaire radio-induite sont controversées et proviennent d’études pour lesquelles sont utilisées des drogues : l’action se produit donc de manière indirecte. Certains suggèrent que l’induction combinée de l’apoptose et de l’autophagie améliore le traitement par radiations ionisantes. D’autres indiquent que l’induction de l’autophagie favoriserait la radiorésistance des cellules tumorales et que l’utilisation d’inhibiteurs de l’autophagie augmenterait la réponse des tumeurs aux radiations ionisantes. L'autophagie, ou «self-eating», est un processus cellulaire activé par diverses conditions de stress, par lequel les cellules peuvent dégrader les protéines et les organites. Nous avons au cours de cette étude cherché à déterminer le rôle de l'autophagie dans la mort cellulaire radio-induite. Selon nos observations, l'autophagie est nécessaire pour la libération de l'ATP après un traitement par radiothérapie: en effet, le knockdown de gènes essentiels à l'autophagie limite la sécrétion d'ATP. Nous avons également constaté que des cellules déficientes pour l'autophagie traitées par radiothérapie sont incapables d’immuniser des souris contre une injection de cellules vivantes. En outre, les tumeurs déficientes pour l’autophagie répondent moins bien à un traitement par radiations ionisantes dans des souris immunocompétentes et continuent à proliférer, contrairement aux tumeurs “wild-type”. De plus, nous avons montré que les cellules déficientes pour l'autophagie ne sont pas en mesure de recruter des cellules dendritiques dans le lit tumoral. A l'inverse, l'inhibition des enzymes de dégradation de l’ATP extracellulaire accroît les concentrations d'ATP dans les tumeurs déficientes pour l'autophagie, ce qui rétablit le recrutement des cellules immunitaires dans le lit tumoral et restaure la réponse à la radiothérapie des cancers déficients pour l'autophagie. Ainsi, cette étude a montré l'importance de l'autophagie dans la réponse anti-tumorale spécifique, après traitement par radiations ionisantes. Ces résultats ouvrent de nouvelles perspectives pour comprendre la mort cellulaire radio-induite. Il reste cependant à découvrir les mécanismes moléculaires sous-jacents pour développer de nouvelles thérapies ciblées qui amélioreront l’efficacité de la radiothérapieMost of the available data on autophagy and tumor response to IR comes from indirect conclusions after concomitant drug-IR exposure. Some authors suggest that concurrent induction of apoptosis and autophagy enhances radiation therapy. Oppositely, others indicate that the induction of autophagy contributes to the radioresistance of tumor cells and suggest that autophagy inhibitors may be employed to increase the sensitivity radioresistant tumors cells to ionizing radiation. Autophagy literally ‘self-eating’ is a cellular process activated in response to various conditions of cellular stress, whereby cells can liberate energy resources via the degradation of proteins and organelles. In this project we aimed to determine the potential role of autophagy in IR –induced cell death. We found that autophagy is required for the release of ATP in response to radiotherapy, as we observed that the knockdown of essential autophagy-related genes abolished its secretion. Furthermore, autophagy deficient tumors growing on immunocompetent mice did not respond to radiotherapy and continued proliferating in contrast to autophagy proficient tumors. We showed that autophagy deficient cells were neither able to recruit DCs into the tumor bed. Conversely, the inhibition of extracellular ATP degrading enzymes increased extracellular ATP concentrations in autophagy deficient tumors, which reestablished the recruitment of immune cells into the tumor bed, and restored radiotherapeutic responses in autophagy-deficient cancers.Altogether, this study showed the importance of autophagy in tumor-specific immune response after radiotherapy. Thus giving new insights into the concept of IR-induced cell death. However, there is still much that is unknown about molecular mechanisms that undergo IR-induced cell death. Understand these molecular mechanisms will help to develop new targeted therapies that will improve the effectiveness of radiotherapy
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Cui, Tao. "Novel Circulating and Tissue Biomarkers for Small Intestine Neuroendocrine Tumors and Lung Carcinoids." Doctoral thesis, Uppsala universitet, Onkologisk endokrinologi, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-205570.
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Small intestine neuroendocrine tumors (SI-NETs) and lung carcinoids (LCs) are relatively indolent tumors, which originate from neuroendocrine (NE) cells of the diffuse NE system. Metastases can spread before diagnosis. Thus, potential cures become unavailable, which entitles new biomarker development. Indeed, we aimed at developing Ma2 autoantibodies and olfactory receptor 51E1 (OR51E1) as potential novel biomarkers and exploring other candidate protein markers in patients’ serum. First, we established a sensitive, specific and reliable anti-Ma2 indirect ELISA to distinguish SI-NET patients from healthy controls. We detected longer progression-free and recurrence-free survivals in patients expressing low anti-Ma2 titers. Moreover, a high anti-Ma2 titer was more sensitive than chromogranin A for the risk of recurrence after radical operation of SI-NET patients. We then investigated OR51E1 expression in SI-NETs and LCs. OR51E1 mRNA expression, analyzed by quantitative real-time PCR, was high in microdissected SI-NET cells, in LC cell lines and in frozen LC specimens. Immunohistochemistry (IHC) showed abundant OR51E1 protein expression in SI-NETs. OR51E1 co-expressed with vesicular-monoamine-transporter-1 in the majority of normal and neoplastic enterochromaffin cells. Furthermore, the study on LCs revealed that OR51E1, somatostatin receptor (SSTR) 2, SSTR3, and SSTR5 are expressed in 85%, 71%, 25% and 39% of typical carcinoids (TCs), whereas in 86%, 79%, 43% and 36% of atypical carcinoids (ACs). Based on the proposed IHC scoring system, in the LC cases, where all SSTR subtypes were absent, membrane OR51E1 expression was detected in 10 out of 17 TCs and 1 out of 2 ACs. Moreover, higher OR51E1 scores were detected in 5 out of 6 OctreoScan-negative LC lesions. In addition, the last presented study used a novel suspension bead array, which targeted 124 unique proteins, by using Human Protein Atlas antibodies, to profile biotinylated serum samples from SI-NET patients and healthy controls. We showed 9 proteins, IGFBP2, IGF1, SHKBP1, ETS1, IL1α, STX2, MAML3, EGR3 and XIAP as significant contributors to tumor classification. In conclusion, we proposed Ma2 autoantibodies as a sensitive circulating marker for SI-NET recurrence; OR51E1 as a candidate therapeutic target for SI-NETs; whereas as a novel diagnostic marker for LCs and 9 serum proteins as novel potential SI-NET markers.小肠神经内分泌肿瘤(SI-NET)和肺类癌(LC)是起源于不同神经内分泌细胞的生长缓慢的肿瘤。肿瘤往往于诊断前已经转移。这导致目前缺乏有效的治疗方法，同时也使得对于新的生物标记物的研发变得有意义。因此，我们在本论文中分别研究了Ma2自身抗体(抗Ma2)，以及潜在的新型生物标记物嗅觉受体51E1(OR51E1)。我们还探讨了患者血清中的其他候选蛋白标记物。 首先，我们建立了一个灵敏特异而可靠的抗Ma2间接酶联免疫吸附试验，用以区分SI-NET患者组和健康对照组。在表达低滴度抗Ma2的患者中，我们检测到了较长的病情无恶化存活率以及肿瘤无复发存活率。此外，高滴度抗Ma2比嗜铬粒蛋白A更为灵敏地检测到了SI-NET患者根治手术后复发的风险。 接下来，我们研究了SI-NET和LC患者肿瘤中的OR51E1受体蛋白的表达。我们用实时定量PCR技术检测到了OR51E1信使核糖核酸在显微切除的SI-NET肿瘤细胞中，以及在LC细胞系和冷冻LC标本中的高度表达。免疫组化结果显示出OR51E1蛋白在SI-NET肿瘤组织中的高度表达。OR51E1与囊泡单胺转运蛋白1在大多数正常和肿瘤的肠嗜铬细胞中可共表达。 另外，我们针对LC患者的研究显示，OR51E1受体蛋白以及促生长素抑制素受体(SSTR)2，SSTR3和SSTR5分别在85％，71％，25％和39％的典型性肺类癌(TC)，以及86％，79％，43％和36的非典型性肺类癌(AC)中表达。基于我们我提出的免疫组化结果得分系统，在无SSTR表达的LC中，OR51E1蛋白在17个TC中的10个以及2个AC中的1个中呈细胞膜表达。而且，在6个OctreoScan显象呈阴性的LC中，有5个OR51E1免疫组化得分很高。 此外，在本论文最后的一项研究中，我们采用了一种新型的悬浮磁珠阵列技术，通过使用来自于人类蛋白质图谱项目的针对124种独特蛋白质的抗体，对SI-NET患者和健康对照组的用生物素标记过的血清样本进行了分析。结果显示，通过利用9种蛋白，即IGFBP2，IGF1，SHKBP1，ETS1，STX2，IL1α，MAML3，EGR3和XIAP，我们可以显著的对肿瘤进行分类。 综上所述，我们提出Ma2自身抗体可作为一个体液中灵敏的生物标记物用以暗示SI-NET肿瘤的复发; OR51E1受体蛋白可作为一个在SI-NET治疗中所能用及的候选生物靶分子，并在LC中作为一种新型的潜在生物标记物。此外，我们在SI-NET患者血清中检测到了9种新的候选标记物蛋白。
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Oliveira, Ana Maia Cerqueira Sarmento. "Molecular Subtyping of Lung Carcinomas for Targeted Therapy." Master's thesis, 2012. https://repositorio-aberto.up.pt/handle/10216/65207.
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Oliveira, Ana Maia Cerqueira Sarmento. "Molecular Subtyping of Lung Carcinomas for Targeted Therapy." Dissertação, 2012. https://repositorio-aberto.up.pt/handle/10216/65207.
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Cheng, Ai-ling, and 程愛淩. "Frequent Inactivation of LKB1 in Human Non-Small Cell Lung Carcinomas." Thesis, 2005. http://ndltd.ncl.edu.tw/handle/89565221110383155096.
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碩士國立中山大學
生物醫學科學研究所
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Lung cancer is the second leading cause of cancer-related death in Taiwan in 2003. However, lung cancer has become the first in 2004. Discovering the new molecular targets may provide new methods for the treatments of this devastating disease. LKB1, a serine/threonine kinase, is a new tumor suppressor gene with spontaneous mutations and/or deletions found in human cancers. Reports have recently demonstrated that LKB1 inactivating mutations in lung adenocarcinomas of sporadic origin, including primary tumors and lung cancer cell lines. In this study, we investigated LKB1 gene inactivation frequencies in 110 Taiwan patients with non-small cell lung carcinomas (NSCLC) and 7 lung cancer cell lines. LKB1 inactivation was screened by polymerase chain reaction (PCR), sequencing, co-amplification and loss of heterozygosity (LOH) analysis. In addition, LKB1 expressions were determined in clinical samples by immunohistochemistry (IHC) and in cell lines by reverse-transcriptase PCR and western blot analysis. The results showed five out of 110 (4.5%) patients with LKB1 gene exon 8 deletions. Two out these 5 patients were also found with exon 7 deletions. An identical mutation at codon 354 (Phe to Leu) were found in 4 out of 65 (6.2%) patients. The nature of this mutation was found to be a new LKB1 polymorphism by single strand conformation polymorphism (SSCP) assay and sequencing analysis after compared to normal controls. Various point mutations were also found in 3 out of 7 cell lines. In addition, 11 out of 81 (13.6%) patients were found with LOH. Finally, reduced expressions of LKB1 were observed in lung cancer clinical samples. These data suggest that LKB1 may be a tumor suppressor gene that involved in the carcinogenesis of NSCLC.