Club cells form lung adenocarcinomas and maintain the alveoli of adult mice
| Autor: | Vassilis Aidinis, Malamati Vreka, Laura V. Klotz, Yuanyuan Chen, Fani Roumelioti, Rocio Sotillo, Dimitrios Toumpanakis, Vasileios Armenis, Spyros Zakynthinos, Anastasios D. Giannou, Magda Spella, Anne-Sophie Lamort, Vassiliki Karavana, Georgios T. Stathopoulos, Antonia Marazioti, Mario A.A. Pepe, Darcy E. Wagner, Kristina A. M. Arendt, Ioannis Lilis, Nikolaos I. Kanellakis, Dimitra E. Zazara, Ioanna Giopanou, Maria Armaka |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Mouse medicine.disease_cause Tobacco smoke Mice 0302 clinical medicine Biology (General) Cancer Biology General Neuroscience General Medicine respiratory system 3. Good health medicine.anatomical_structure 030220 oncology & carcinogenesis Medicine KRAS Research Article Human Cell Survival QH301-705.5 Science urethane Adenocarcinoma of Lung Respiratory Mucosa Lung injury General Biochemistry Genetics and Molecular Biology Alveolar cells chemical carcinogenesis 03 medical and health sciences Tobacco Smoking medicine Animals airway transcriptome Lung cancer Carcinogen Cell Proliferation Lung General Immunology and Microbiology business.industry Airway Transcriptome Cell Biology Chemical Carcinogenesis Lung Adenocarcinoma Urethane Epithelial Cells Environmental Exposure medicine.disease lung adenocarcinoma respiratory tract diseases Pulmonary Alveoli Disease Models Animal 030104 developmental biology Carcinogens Cancer research business Carcinogenesis |
| Zdroj: | eLife, Vol 8 (2019) eLife 8:e45571 (2019) eLife |
| ISSN: | 2050-084X |
| Popis: | Lung cancer and chronic lung diseases impose major disease burdens worldwide and are caused by inhaled noxious agents including tobacco smoke. The cellular origins of environmental-induced lung tumors and of the dysfunctional airway and alveolar epithelial turnover observed with chronic lung diseases are unknown. To address this, we combined mouse models of genetic labeling and ablation of airway (club) and alveolar cells with exposure to environmental noxious and carcinogenic agents. Club cells are shown to survive KRAS mutations and to form lung tumors after tobacco carcinogen exposure. Increasing numbers of club cells are found in the alveoli with aging and after lung injury, but go undetected since they express alveolar proteins. Ablation of club cells prevents chemical lung tumors and causes alveolar destruction in adult mice. Hence club cells are important in alveolar maintenance and carcinogenesis and may be a therapeutic target against premalignancy and chronic lung disease. eLife digest The deadliest form of lung cancer is called lung adenocarcinoma, or LUAD. Tobacco chemicals often cause the disease by damaging the genetic information of lung cells. The damage leads to harmful changes in the DNA sequence which prompt the cells to form tumors. For instance, the most common of these changes takes place in a gene called KRAS. However, it is still unclear exactly which type of lung cells are more likely to develop into a tumor. In the lungs, airway epithelial cells cover the inside of the passages that bring the air inside little sacks called alveoli, which are lined by alveolar cells. Previous studies have used genetic methods to switch on the KRAS mutation in different compartments of the mouse lung. This showed that groups of airway cells, of alveolar cells, and of a class of cells located at the junction between airways and alveoli could all give rise to cancer. However, these experiments did not examine how tobacco chemicals could give rise to tumors in different groups of lung cells. Here, Spella et al. triggered LUAD in adult mice by exposing them to the toxic chemicals found in tobacco smoke, but without making any change to the KRAS gene. These mice also had genetically engineered reporters that could be used to deduce where the resulting tumors came from. DNA sequencing showed that the airway epithelial cells gained KRAS mutations after the chemical treatment. When the airway epithelial cells were experimentally removed before the treatments with tobacco chemicals, these mice did not get LUAD tumors. Spella et al. also observed that the tobacco-induced tumors came from the epithelial cells in the airways, and not from the cells in the alveoli. Moreover, when the lung was damaged, airway cells could move to the alveoli and start adopting the identity of alveolar cells, thereby replenishing this population. Together, these experiments imply that tobacco-induced LUAD starts in the airway epithelial cells. These findings suggest that airway epithelial cells could be targeted to stop lung cancer early on. Further studies should also examine how airway epithelial cells can transition to look more like alveolar cells when the lungs get harmed. |
| Databáze: | OpenAIRE |
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