Contexte : Le cancer du poumon est le cancer le plus associé aux expositions professionnelles. Bien que l’amiante soit sans doute le facteur étiologique professionnel le plus connu, plusieurs éléments suggèrent également l’implication de facteurs modifiables d’origine environnementale ou professionnelle, beaucoup plus rarement étudiés, parmi lesquels les agents biologiques. Si les endotoxines - toxines situées dans la membrane externe des bacilles Gram négatif - sont fréquemment associées à une réduction du risque de cancer du poumon, les infections à papillomavirus humains sont suspectées d’augmenter ce risque. Les résultats des études épidémiologiques sur le sujet sont divergents et sont régulièrement limités par de nombreuses faiblesses méthodologiques incluant entre autres la non prise en compte du tabagisme et de l’exposition à l’amiante.Objectifs : L’objectif de cette thèse est d’étudier le rôle des agents biologiques présents sur les lieux de travail dans la survenue des cancers broncho-pulmonaires. Plus spécifiquement, les objectifs de ce travail sont : (1) d’étudier le rôle de l’exposition professionnelle aux endotoxines sur le risque de cancer du poumon, d’évaluer les aspects de la relation dose-effet ainsi que les interactions possibles avec les antécédents des maladies respiratoires; (2) de s’intéresser plus particulièrement à l’industrie textile, source de fortes expositions aux endotoxines, en étudiant le risque de cancer du poumon associé à l’exposition professionnelle aux poussières textiles ; (3) d’étudier le risque de cancer du poumon dans l’industrie de la viande en testant, notamment l’hypothèse d’une exposition à un agent viral.Population et méthodes : Ce travail s’est appuyé sur les données de l’étude cas-témoins en population générale ICARE. Les cas de cancer du poumon ont été identifiés dans 10 départements français abritant un registre général de cancer. Au total, 2276 cas de cancer du poumon et 2780 témoins hommes ont été inclus ainsi que 650 cas de cancers du poumon et 775 témoins femmes. Les descriptions détaillées de l’histoire professionnelle complète recueillies par des questionnaires standardisés ont permis de coder les professions et les secteurs d’activités de chaque emploi selon les classifications CITP 1968 et NAF 2000.Résultats : Nous avons trouvé une association inverse entre les expositions professionnelles aux endotoxines et le risque de cancer du poumon particulièrement plus marquée chez les travailleurs de l’élevage (tous types) et de la collecte et traitements des déchets. Les odds ratios de cancer du poumon diminuent avec la durée et l’indice cumulé d’exposition aux endotoxines. Nos résultats ne soutiennent pas l'existence d'une forte association entre l'exposition professionnelle aux poussières textiles et le cancer du poumon, néanmoins, ils montrent une diminution significative de 30% du risque de cancer du poumon chez les travailleurs du coton avec OR= 0,7 ; IC 95% [0,5-0,9]. Par ailleurs, nous observons une association positive significative avec le risque de cancer du poumon chez les travailleurs de l’industrie de la viande (OR= 1,46 [1,0-2,1]). Cependant, les antécédents de verrues de la main ne semblent pas avoir d’effet modificateur dans l’association entre le travail dans l’industrie de la viande et le risque de cancer du poumon.Conclusion : Nos résultats soutiennent le rôle important des expositions professionnelles comme déterminants du risque de cancer du poumon. Ils confirment les associations inverses entre les expositions aux endotoxines et le risque de cancer du poumon suggérant fortement l’hypothèse d’un effet anti-tumoral des endotoxines vis-à-vis du poumon. Par ailleurs, ils semblent indiquer que le travail dans l’industrie de la viande est une situation d’exposition à risque de cancer du poumon sans toutefois conclure formellement quant à l’implication des infections à papillomavirus humains. / Background: Lung cancer is the most common cancer associated with occupational exposures. Although asbestos is the best known occupational etiologic factor, several hypotheses suggest the involvement of some environmental or occupational modifiable factors, much more rarely studied, including biological agents. Endotoxins-toxins being part of the outer membrane of Gram-negative bacilli- are commonly associated with reduced risk of lung cancer, while human papillomavirus infections are suspected of increasing the risk. However, the majority of published studies had small numbers of cases and some methodological issues such as inadequate adjustment for tobacco smoking and occupational exposure to asbestos.Objectives: The aim of the present work is to study the role of biological agents found in the workplace on lung cancer risk and more specifically: (1) to investigate the role of occupational exposure to endotoxins on lung cancer risk, to assess dose-response relationship aspects and possible interactions with history of respiratory disease; (2) to focus on the textile industry, which is a source of high exposure to endotoxins, by examining the risk of lung cancer associated with occupational exposure to textile dust; (3) to study the risk of lung cancer in the meat industry by testing the hypothesis of an exposure to a viral agent.Population and methods: This work was based on a large population-based case-control study, ICARE. Cases and controls were recruited from 10 French departments. Incident cases were identified through French cancer registries. A total of 2,926 lung cancer cases (2,276 men and 650 women) and 3,555 controls (2,780 men and 775 women) were included. Detailed information on lifetime occupation was collected through standardized questionnaires. Jobs and sectors were coded according to the ISCO 1968 and the NAF 2000 classifications.Results: Our results showed an inverse association between exposure to endotoxins and lung cancer risk particularly among livestock (all types) and waste collection and treatment workers. Negative trends were shown with duration and cumulative exposure. Furthermore, our findings do not the existence of strong association between occupational exposure to textile dust and lung cancer. A decreased risk was suggested for distant exposures and for work with cotton fibres (OR = 0.7; 95% CI [0.5-0.9]). On the other hand, we observe a significantly increased risk among meat workers OR = 1.46 [1.1-2.1]). However, the history of hand warts does not seem to have any modifying effect on the association between work in the meat industry and the risk of lung cancer.Conclusion: Our findings support the important role of occupational exposures as a determinant of lung cancer risk. This confirms the inverse associations between endotoxin exposures and the risk of lung cancer strongly suggesting an anti-tumor effect of endotoxins towards the lung. This also seems to indicate that working in the meat industry is a risky situation for lung cancer without, however, formally concluding about the involvement of human papillomavirus infections.

Polycyclic aromatic hydrocarbons (PAHs) comprise an important class of environmental pollutants that are known to cause lung cancer in animals and suspected lung carcinogens in humans. PAHs are also known to cause cancer in offspring when provided to a pregnant mouse. Some evidence from cell-based studies points to PAHs as modulators of the epigenome, that is modifications to DNA structure that control the expression of genes. Inappropriate changes to the epigenome and consequently expression of cancer-critical genes are often characteristic of cancer cells. The objective of this thesis research was to determine the impact of transplacental exposure to two model PAHs on the epigenome of fetal and adult lung tissues in offspring. Specifically, we measured patterns of methylation of DNA, a type of epigenetic mark, in different types of lung tissue to assess changes in the epigenome associated with development of lung cancer. Two strategies were employed: 1) a targeted approach using ultra-deep bisulfite sequencing to precisely measure the specific pattern of methylated sites in the promoter regulatory region for several tumor suppressor genes, including Cdkn2a, Rarb, Dapk1 and Mgmt; and 2) a broad, genome-wide approach using a microarray covering all regulatory promoter regions in the entire mouse genome. Our first approach did not yield any marked differences in methylation patterns for any of the target genes for lung tissues obtained at birth or at various ages up to 45 weeks, nor according to the type of tissue (normal, pre-neoplastic, tumor). However, the genome-wide approach did yield specific patterns of methylation in lung tumors, including distinct profiles associated with lung tumor tissue from PAH-exposed animals that were substantially different from normal lung tissue in control animals. Altogether, the research presented here identified several new target genes of interest for future studies investigating the epigenetics of PAHinitiated lung cancer. This work also provided new knowledge that exposure to PAHs can lead to distinct DNA methylation profiles in lung tumors in adult offspring.

Proper lung function relies on the precise balance of specialized epithelial cell types that coordinate to maintain homeostasis. The Hippo pathway has emerged as a critical regulator of cell fate both developmentally and in a regenerative setting. The work presented in this dissertation describes essential roles for the transcriptional effectors of Hippo pathway signaling, Yap and Taz, in maintaining lung epithelial homeostasis. The data presented here demonstrate that conditional deletion of Yap and Wwtr1/Taz in the lung epithelium of adult mice results in severe defects with consequent animal lethality. Phenotypes associated with Yap/Taz deletion include alveolar disorganization, a development of mucin hypersecretion throughout the airways, and ciliary disorganization. Through in vivo lineage tracing, analysis of mouse and human tissues, along with in vitro molecular experiments, these studies show that nuclear YAP/TAZ exert transcriptional control over club cell fate, while in multiciliated cells, they function within the cytoplasm to maintain ciliary structures. Within club cells, reduced YAP/TAZ activity promotes intrinsic goblet transdifferentiation of secretory airway epithelial cells. Global gene expression and ChIP-Seq analyses reveal that YAP/TAZ act through the TEAD family of transcription factors to suppress a goblet cell differentiation program in airway epithelial cells, including direct repression of the SPDEF gene, which encodes a transcription factor required for goblet cell identity. Further in vitro studies identify cooperation between YAP/TAZ-TEAD and the NuRD chromatin remodeling complex to inhibit SPDEF expression and that Hippo-regulated YAP/TAZ impinge on cytokine-induced goblet cell differentiation. Within multiciliated cells, we observe that phosphorylated Yap localizes in a planar polarized manner at the base of cilia and controls ciliary and basal body density. Lineage specific Yap/Taz deletion leads to reduced ciliary density and height due to a loss of apically basal bodies. Collectively, this work identifies YAP/TAZ as critical factors in lung epithelial homeostasis and offers new molecular insight into the mechanisms regulating the secretory and multiciliated cell lineages, which are frequently impaired in a broad range of lung diseases. / 2024-02-02T00:00:00Z

Pancoast tumors are a distinct entity seen mostly in non-small cell carcinoma of the lung. We present a case of a Pancoast tumor in newly diagnosed squamous cell carcinoma of the lung. A 56-year old female with a 40-pack year smoking history, presented with several weeks duration of right shoulder pain, radiating down her arm. Symptoms were aggravated with movement and slightly improved with rest and non-steroidal analgesics She had no other known medical history. Physical therapy provided little relief. Subsequently, magnetic resonance imaging (MRI) of the cervical spine from an outside facility revealed a large right apical lung mass, involving the T2 thoracic spine and sternum. She denied chest pain, shortness of breath, weight loss, or edema of the face or neck. Range of motion of right upper extremity was limited due to pain. Ptosis and miosis of the right eye were detected. Days after the MRI, the patient presented to the hospital for intractable right upper extremity pain. Comprehensive imaging including positron emission tomography scan and MRI of the brain were done. The right apical lung mass was suggestive of a Pancoast tumor, measuring 5.3 x 5.5 x 6.9 cm in size, extending into the medial portion of the upper mediastinum. The tumor abutted the apical pleura and partially encased the right subclavian artery. There was destruction of the first and second ribs and portions of the right T1 and T2 vertebral bodies along with right hilar and lower paratracheal adenopathy. Biopsy of the mass confirmed moderately differentiated, invasive squamous cell carcinoma of the lung, assessed to be Stage IIIB and unresectable. Pain control was achieved, and the patient was discharged. Treatment was initiated with concurrent radiation and chemotherapy with cisplatin and etoposide. Pancoast tumors, also known as superior sulcus tumors, were first noted in 1838 but not well defined at the time. In 1924 and 1932, American radiologist, Henry Pancoast, further described them as carcinomas of unknown origin of the chest apex. They occur in 3-5% of lung cancers, most commonly in non-small cell carcinoma. By definition, a Pancoast tumor must invade parietal pleura and cause pain, paresthesia, or neurologic dysfunction. Less than 50% of these tumors are resectable. They may involve the lower cervical and/or upper thoracic spines, first and second ribs, brachial plexus, and subclavian vessels. Involvement of paravertebral sympathetic chains can lead to Horner syndrome with a prevalence up to 40%. Neurologic compromise may cause upper extremity weakness, muscular atrophy, and paresthesia. In 5% of cases, they can cause spinal cord compression and paraplegia. Five-year survival is reported to be less than 10% if there is vertebral body invasion. In locally advanced lung cancers including Pancoast tumors, treatment can include neoadjuvant chemoradiation with subsequent resection. However due to the extensiveness and complexity of this patient’s tumors, resection was not amenable. Evaluation for Pancoast tumor may be warranted in those with lung cancer risk with acute musculoskeletal/neurologic complaints. Treatment is initiated promptly, based on stage and histology.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18452号 / 医博第3907号 / 新制||医||1004(附属図書館) / 31330 / 京都大学大学院医学研究科医学専攻 / (主査)教授 伊達 洋至, 教授 武田 俊一, 教授 富樫 かおり / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18861号 / 医博第3972号 / 新制||医||1008(附属図書館) / 31812 / 京都大学大学院医学研究科医学専攻 / (主査)教授 武藤 学, 教授 野田 亮, 教授 小川 誠司 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・論文博士 / 博士(医学) / 乙第12970号 / 論医博第2103号 / 新制||医||1012(附属図書館) / 32408 / 新制||医||1012 / 京都大学大学院医学研究科医学専攻 / (主査)教授 小池 薫, 教授 三嶋 理晃, 教授 中山 健夫 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DGAM

京都大学 / 0048 / 新制・論文博士 / 博士(医学) / 乙第13000号 / 論医博第2108号 / 新制||医||1016(附属図書館) / 32928 / (主査)教授 森田 智視, 教授 武藤 学, 教授 中山 健夫 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19620号 / 医博第4127号 / 新制||医||1015(附属図書館) / 32656 / 京都大学大学院医学研究科医学専攻 / (主査)教授 武藤 学, 教授 森田 智視, 教授 山下 潤 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(薬学) / 甲第19654号 / 薬博第824号 / 新制||薬||240(附属図書館) / 32690 / 京都大学大学院薬学研究科薬学専攻 / (主査)教授 松原 和夫, 教授 中山 和久, 教授 金子 周司 / 学位規則第4条第1項該当 / Doctor of Pharmaceutical Sciences / Kyoto University / DFAM