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Nature Mar 2014Alveoli are gas-exchange sacs lined by squamous alveolar type (AT) 1 cells and cuboidal, surfactant-secreting AT2 cells. Classical studies suggested that AT1 arise from...
Alveoli are gas-exchange sacs lined by squamous alveolar type (AT) 1 cells and cuboidal, surfactant-secreting AT2 cells. Classical studies suggested that AT1 arise from AT2 cells, but recent studies propose other sources. Here we use molecular markers, lineage tracing and clonal analysis to map alveolar progenitors throughout the mouse lifespan. We show that, during development, AT1 and AT2 cells arise directly from a bipotent progenitor, whereas after birth new AT1 cells derive from rare, self-renewing, long-lived, mature AT2 cells that produce slowly expanding clonal foci of alveolar renewal. This stem-cell function is broadly activated by AT1 injury, and AT2 self-renewal is selectively induced by EGFR (epidermal growth factor receptor) ligands in vitro and oncogenic Kras(G12D) in vivo, efficiently generating multifocal, clonal adenomas. Thus, there is a switch after birth, when AT2 cells function as stem cells that contribute to alveolar renewal, repair and cancer. We propose that local signals regulate AT2 stem-cell activity: a signal transduced by EGFR-KRAS controls self-renewal and is hijacked during oncogenesis, whereas another signal controls reprogramming to AT1 fate.
Topics: Animals; Cell Differentiation; Cell Division; Cell Lineage; Cell Transformation, Neoplastic; Cells, Cultured; Cellular Reprogramming; Clone Cells; ErbB Receptors; Female; Lung; Lung Neoplasms; Male; Mice; Models, Biological; Multipotent Stem Cells; Proto-Oncogene Proteins p21(ras); Pulmonary Alveoli; Regeneration; Signal Transduction
PubMed: 24499815
DOI: 10.1038/nature12930 -
Nature Jul 2023Many cancers originate from stem or progenitor cells hijacked by somatic mutations that drive replication, exemplified by adenomatous transformation of pulmonary...
Many cancers originate from stem or progenitor cells hijacked by somatic mutations that drive replication, exemplified by adenomatous transformation of pulmonary alveolar epithelial type II (AT2) cells. Here we demonstrate a different scenario: expression of KRAS(G12D) in differentiated AT1 cells reprograms them slowly and asynchronously back into AT2 stem cells that go on to generate indolent tumours. Like human lepidic adenocarcinoma, the tumour cells slowly spread along alveolar walls in a non-destructive manner and have low ERK activity. We find that AT1 and AT2 cells act as distinct cells of origin and manifest divergent responses to concomitant WNT activation and KRAS(G12D) induction, which accelerates AT2-derived but inhibits AT1-derived adenoma proliferation. Augmentation of ERK activity in KRAS(G12D)-induced AT1 cells increases transformation efficiency, proliferation and progression from lepidic to mixed tumour histology. Overall, we have identified a new cell of origin for lung adenocarcinoma, the AT1 cell, which recapitulates features of human lepidic cancer. In so doing, we also uncover a capacity for oncogenic KRAS to reprogram a differentiated and quiescent cell back into its parent stem cell en route to adenomatous transformation. Our work further reveals that irrespective of a given cancer's current molecular profile and driver oncogene, the cell of origin exerts a pervasive and perduring influence on its subsequent behaviour.
Topics: Humans; Adenocarcinoma of Lung; Cellular Reprogramming; Lung Neoplasms; Proto-Oncogene Proteins p21(ras); Stem Cells; Extracellular Signal-Regulated MAP Kinases
PubMed: 37468622
DOI: 10.1038/s41586-023-06324-w -
Food Safety (Tokyo, Japan) Mar 2020FSCJ conducted a risk assessment of fluxametamide (CAS No. 928783-29-3), an isoxazoline insecticide, based on results from various studies. The data used in the...
FSCJ conducted a risk assessment of fluxametamide (CAS No. 928783-29-3), an isoxazoline insecticide, based on results from various studies. The data used in the assessment include the fate in animals, fate in plants, residues in crops, subacute toxicity, subacute neurotoxicity, chronic toxicity, combined chronic toxicity/carcinogenicity, carcinogenicity, two-generation reproductive toxicity, developmental toxicity, and genotoxicity. Alveolar macrophage accumulation, vacuolated epithelial cells in the small intestine, and hepatocellular vacuolation are observed in various toxicity studies. Increased incidences of thyroid follicular cell adenoma in male rats and of hepatocellular adenoma in male mice were observed in carcinogenicity studies. However, a genotoxic mechanism was unlikely to be involved in the tumor increases. FSCJ specified an acceptable daily intake (ADI) of 0.0085 mg/kg bw per day, applying a safety factor of 100 to the NOAEL, 0.85 mg/kg bw per day, that was derived from the two-year combined chronic toxicity/carcinogenicity study in rats.
PubMed: 32231959
DOI: 10.14252/foodsafetyfscj.D-20-00006 -
Jornal Brasileiro de Pneumologia :... 2006Alveolar adenoma is a rare benign neoplasm of the lungs, and very few cases have been described in the literature. Patients with alveolar adenoma are frequently...
Alveolar adenoma is a rare benign neoplasm of the lungs, and very few cases have been described in the literature. Patients with alveolar adenoma are frequently asymptomatic and are diagnosed through the accidental discovery of a singular, well-delineated nodule on a routine chest X-ray. The definitive diagnosis is made histologically, and the treatment consists of surgical resection of the nodule.
Topics: Adenoma; Adult; Female; Humans; Lung Neoplasms; Thoracotomy; Tomography, X-Ray Computed
PubMed: 17273617
DOI: 10.1590/s1806-37132006000300014 -
Pathologica Aug 2022Alveolar adenoma is a rare tumour of the lung. It is typically found in asymptomatic adults as a peripheral or subplerual nodule on imaging examination. Microscopically,... (Review)
Review
Alveolar adenoma is a rare tumour of the lung. It is typically found in asymptomatic adults as a peripheral or subplerual nodule on imaging examination. Microscopically, the tumour is composed of admixture of epithelial and mesenchymal component in variable sized cystic or alveolar structures. The tumour shows a benign nature. There have been no reported recurrences or metastases. Malignant transformation of alveolar adenoma and coexisting with lung carcinoma have been rarely described. In this article, we report a case of an alveolar adenoma and coexisting atypical adenomatous hyperplasia. This case, contributing to the limited numbers of cases described to date, illustrates the importance of awareness on the possibility of alveolar adenoma being associated with lung carcinoma and its precursor lesions especially when diagnosed by small biopsy specimens.
Topics: Adenoma; Adult; Carcinoma; Humans; Hyperplasia; Lung Neoplasms; Precancerous Conditions
PubMed: 36136901
DOI: 10.32074/1591-951X-755 -
International Journal of Clinical and... Nov 2010Bronchioloalveolar carcinoma (BAC) arising in the peripheral lung is the prototype of human lung adenocar-cinoma and is considered to develop, at least in part, from its...
Bronchioloalveolar carcinoma (BAC) arising in the peripheral lung is the prototype of human lung adenocar-cinoma and is considered to develop, at least in part, from its precursor atypical adenomatous hyperplasia (AAH). Molecular genetics investigations have revealed the significant roles of mutations in KRAS and epidermal growth factor receptor (EGFR) genes in the pathogenesis of AAH and BAC. Recently, selective molecular targeting therapies, such as those using EGFR tyrosine kinase inhibitors, have been introduced with remarkable success. In spite of the accumulation of research results into BAC/AAH, there remain three important issues to be addressed; 1) the etiology of BAC and AAH, 2) the genetic and/or epigenetic alteration(s) responsible for the progression of AAH to BAC, 3) the genetic backgrounds speculated as the cause of multiple AAH/BAC. These three issues are briefly reviewed and discussed, along with the murine pulmonary carcinogenesis model which is potentially useful for solving these issues.
Topics: Adenocarcinoma, Bronchiolo-Alveolar; Adenoma; Animals; Disease Models, Animal; ErbB Receptors; Hyperplasia; Lung Neoplasms; Mice; Mutation; Precancerous Conditions; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); ras Proteins
PubMed: 21228931
DOI: No ID Found -
Canadian Association of Radiologists... May 2016Pulmonary opacities/nodules are common findings on computed tomography examinations, which may represent an underlying infections or malignancy. However, not every... (Review)
Review
Pulmonary opacities/nodules are common findings on computed tomography examinations, which may represent an underlying infections or malignancy. However, not every pulmonary nodule or opacity represents malignancy or infection. We present a pictorial essay illustrating common as well as obscure noninfectious, nonmalignant pulmonary lesions. Lesions discussed include organizing pneumonia, Langerhans cell histiocytosis, pulmonary amyloidosis, hyalinizing granuloma, tumourlet (benign localized neuroendocrine cell proliferations), atypical alveolar hyperplasia, inflammatory myofibroblastic tumour, papillary alveolar adenoma, plasma cell granuloma, juvenile xanthogranuloma, and sclerosing hemangiomas. We discuss the clinical presentation, prevalence, radiographic clues, pathology, and diagnostic pitfalls of these rare lesions.
Topics: Humans; Lung; Lung Diseases; Tomography, X-Ray Computed
PubMed: 26690551
DOI: 10.1016/j.carj.2015.07.004 -
The Journal of International Medical... Jun 2013Alveolar adenoma is an extremely rare and benign pulmonary neoplasm; it is always asymptomatic and is usually detected incidentally on routine chest X-radiography.... (Review)
Review
Alveolar adenoma is an extremely rare and benign pulmonary neoplasm; it is always asymptomatic and is usually detected incidentally on routine chest X-radiography. Typically on imaging examinations, alveolar adenoma exhibits as a peripheral, solitary, cystic nodule in the lung, which may easily imitate other lung lesions, consequently leading to difficulties in the differential diagnosis of this condition. Surgical resection is the primary treatment option. The diagnosis of alveolar adenoma is mainly based on postoperative histopathology, with features of proliferative type 2 alveolar epithelial cells and septal mesenchyme. The present case was a 60-year-old woman with alveolar adenoma, combined with systemic mutifocal cystic lesions. She underwent surgery following the obvious enlargement of this mass and a cystic nodule 7 cm in maximum diameter was resected. Postoperative histopathology confirmed a diagnosis of alveolar adenoma; her prognosis was favourable. In addition to reporting a rare case of alveolar adenoma coexisting with multifocal cysts, the English-language literature was reviewed for similar cases of alveolar adenoma.
Topics: Adenoma; Adult; Aged; Alveolar Epithelial Cells; Cysts; Diagnosis, Differential; Female; Humans; Lung Neoplasms; Male; Middle Aged; Pulmonary Alveoli; Radiography; Solitary Pulmonary Nodule
PubMed: 23653367
DOI: 10.1177/0300060513477304 -
Medicine Dec 2023To analyze the clinical-pathological characteristics of 3 cases of bronchiolar adenoma/pulmonary ciliary mucinous nodular papillary tumors, and to improve the... (Review)
Review
OBJECTIVE
To analyze the clinical-pathological characteristics of 3 cases of bronchiolar adenoma/pulmonary ciliary mucinous nodular papillary tumors, and to improve the understanding of bronchiolar adenoma (BA)/ciliated muconodular papillary tumors (CMPT) (bronchiolar adenoma/ciliated muconodular papillary tumor).
METHODS
Retrospective analysis was done on the clinical information, diagnosis, and treatment of 3 instances of BA/CMPT at the Second People's Hospital of Weifang City. By scanning the CNKI, Wanfang, VIP database, and Pubmed database using the English key words "bronchiolar adenoma, ciliated muconodular papillary tumor," respectively patients with comprehensive clinical data were gathered, and studies from January 2002 to August 2021 that were relevant to the patients were examined.
RESULTS
A total of 35 articles and 71 instances were found, including 3 cases in our hospital, for a total of 74 cases. There were 31 males and 43 females among them, ranging in age from 18 to 84 years (average 63 years), and 15 cases had a smoking history. The majority of them were discovered by physical examination and had no clinical symptoms. The majority of the imaging revealed solid nodules with variable forms, with some ground-glass nodules displaying vacuole and bronchial inflation signs. BA/CMPT are generally gray-white, gray-brown solid nodules with obvious boundaries but no envelope with a maximum dimension of 4 to 45 mm (average 10.6 mm) on gross examination. Acinar, papillary, and lepidic formations can be seen under the microscope at high magnification; the majority of these structures are made up of tripartite epithelial components, including basal cells, mucous cells, ciliated columnar cells, and alveolar epithelial cells, demonstrating a variety of combinations. An important basis for diagnosis in immunohistochemistry is the continuous positive basal cell layer that is shown by p63, p40, and CK5/6. BRAF and epidermal growth factor receptor are the genes that are most frequently mutated. All of the patients showed no signs of metastasis or recurrence during follow-up period.
CONCLUSION
BA/CMPT is a rare benign tumor of lung epithelium. Because imaging and intraoperative cryosection diagnosis are easy to be misdiagnosed as malignant, it is necessary to further improve understanding and improve immunohistochemistry and genetic examination.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Female; Humans; Male; Middle Aged; Young Adult; Adenoma; Bronchioles; Epithelial Cells; Lung Neoplasms; Neoplasms, Cystic, Mucinous, and Serous; Retrospective Studies; Case Reports as Topic
PubMed: 38115282
DOI: 10.1097/MD.0000000000036559 -
Revista Portuguesa de Pneumologia 2004Adenomas of solitary gland type together with papillomas are the true benign tumours in or around the bronchial tree. Alveolar adenoma and papillary adenoma are more... (Review)
Review
Adenomas of solitary gland type together with papillomas are the true benign tumours in or around the bronchial tree. Alveolar adenoma and papillary adenoma are more frequently observed in peripheral parenchime although this group of tumours is very rare and often incidentally diagnosed. Presenting usually as solitary nodules in adults after 45 years, are easily recognized because of distinct morphology but alveolar adenomas may be difficult to evaluate in frozen sections. Two cases of pleomorphic adenoma and alveolar adenoma are presented and a review of literature is made.
Topics: Adenoma; Bronchial Neoplasms; Female; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasms, Multiple Primary
PubMed: 15300313
DOI: 10.1016/s0873-2159(15)30573-0