Calcitonin driven v-Ha-ras induces multilineage pulmonary epithelial hyperplasias and neoplasms

Sunday, Mary E.; Haley, Kathleen J.; Sikorski, Kristan A.; Graham, S. A.; Emanuel, Rodica L.; Zhang, Fan; Mu, QiQi; Shahsafaei, Aliakbar; Hatzis, Dimitrios

doi:10.1038/sj.onc.1202810

Cited by 29 publications

(18 citation statements)

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“…However, many if not most tumours are composed of multiple histological types (Thurlbeck and Churg, 1995;Fraire et al, 1987). Such variation in a presumably clonal lesion has led to the suggestion that lung cancers arise from a multipotential stem cell component of the normal tissue, a hypothesis supported by the analysis of model systems (Sunday et al, 1999). It is very likely that transcript profiling will lead to further subdivisions within these overall classes of disease, some which mirror preexisting pathological classes and some which are novel (Garber et al, 2001;Bhattacharjee et al, 2001).…”

Section: Introductionmentioning

confidence: 84%

Expression profiling of primary non-small cell lung cancer for target identification

et al. 2002

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Using a panel of cDNA microarrays comprising 47 650 transcript elements, we have carried out a dual-channel analysis of gene expression in 39 resected primary human non-small cell lung tumours versus normal lung tissue. Whilst *11 000 elements were scored as differentially expressed at least twofold in at least one sample, 96 transcripts were scored as over-represented fourfold or more in at least seven out of 39 tumours and 30 sequences 16-fold in at least two out of 39 tumours, including 24 transcripts in common. Transcripts (178) were found under-represented fourfold in at least seven out of 39 tumours, 31 of which are underrepresented 16-fold in at least two out of 39 lesions. The relative expression levels of representative genes from these lists were analysed by comparative multiplex RT -PCR and found to be broadly consistent with the microarray data. Two dramatically over-represented genes, previously designated as potential tumour suppressors in breast (maspin) and lung and breast (S100A2) cancers, were analysed more extensively and demonstrate the effectiveness of this approach in identifying potential lung cancer diagnostic or therapeutic targets. Whilst it has been reported that S100A2 is downregulated in NSCLC at an early stage, our microarray, cmRT -PCR, Western and immunohistochemistry data indicate that it is strongly expressed in the majority of tumours.

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Section: Introductionmentioning

confidence: 84%

Expression profiling of primary non-small cell lung cancer for target identification

et al. 2002

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“…Thus they concluded that lung tumorigenesis can progress through other genetic pathways not requiring activation of the K-ras oncogene. A more recent study that used transgenic models showed a role of v-Has-ras in the induction of multilineage pulmonary epithelial hyperplasia and neoplasia (85).…”

Section: Molecular Studiesmentioning

confidence: 99%

Atypical Adenomatous Hyperplasia of the Lung: A Probable Forerunner in the Development of Adenocarcinoma of the Lung

et al. 2001

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An increasingly large body of work suggests that atypical adenomatous hyperplasia (AAH) of the lung may be a forerunner of pulmonary adenocarcinoma. Recognizing this fact, the World Health Organization now acknowledges the existence of AAH while noting difficulties that may be encountered in distinguishing AAH from the nonmucinous variant of bronchioloalveolar carcinoma. Regrettably, a universally acceptable definition of morphologic criteria for the diagnosis of AAH has not been achieved. This review of the literature examines the epidemiology, gross appearance, light microscopic findings, morphometry, immunohistochemistry, and molecular features of AAH and suggests a set of histopathologic features that may help the practicing pathologist identify this intriguing lesion. These features include the following: irregularly bordered focal proliferations of atypical cells spreading along the preexisting alveolar framework; prominent cuboidal to low columnar alveolar epithelial cells with variable degree of atypia but less than that seen in adenocarcinoma; increased cell size and nuclearcytoplasmic ratio with hyperchromasia and prominent nucleoli, generally intact intercellular attachment of atypical cells with occasional empty-looking spaces between them without high cellularity and without tufting or papillary structures; and slight thickening of the alveolar walls on which the AAH cells have spread, with some fibrosis but without scar formation or significant chronic inflammation of the surrounding lung tissue. Several lines of evidence indicate that AAH is a lesion closely associated with adenocarcinoma of the lung, suggesting AAH may be involved in the early stage of a complex multistep carcinogenesis of pulmonary adenocarcinoma.

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“…On the other hand, it appears that PNECs may renew themselves but do not contribute to epithelial cells in experimental models that cause Clara cell injury (10). Although PNECs are very rare in normal adult lungs, hyperplasias emerge during many human inflammatory processes, as well as in animal models (11)(12)(13)(14)(15). For instance, PNECs may be involved, directly or indirectly, in the pathogenesis of cystic fibrosis (16) and diffuse idiopathic pulmonary neuroendocrine cell hyperplasia in adults (17)(18)(19), and in neuroendocrine cell hyperplasia of infancy (20).…”

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confidence: 99%

Multidirectional Differentiation of Achaete–Scute Homologue–1–Defined Progenitors in Lung Development and Injury Repair

Linnoila

2012

Am J Respir Cell Mol Biol

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Multiple cells contribute to the function of lungs. Pulmonary neuroendocrine cells (PNECs) are important for the regulation of breathing and carcinogenesis, although they represent only a small population of the airway lining. Achaete-Scute homologue-1 (Ascl1), a proneural basic helix-loop-helix transcription factor, is critical for the development of PNECs. We postulated that Ascl1-defined cells (ASDCs) may be progenitors, and traced their fate during development and injury repair. R26R-stop-lacZ (Rosa) reporter mice were crossed with Ascl1-Cre or Ascl1-CreERTM mice, in which the Ascl1 promoter drives the expression of Cre or inducible Cre recombinase, respectively. ASDCs and their descendants will be permanently labeled. The labeled cells were characterized by immunohistochemistry, using highly specific differentiation markers. Lineage studies revealed a population that proliferates before the pseudoglandular stage, and widely contributes to different compartments. When ASDCs were labeled on Embryonic Day 9.5, they gave rise to both airway and alveolar cells, but when labeled on Embryonic Day 11.5, they only gave rise to airway cells. In postnatal naphthalene injury, ASDCs contributed to regenerating Clara cells. In conclusion, Ascl1-defined cells in the lung represent a novel multipotent lineage, indicating a close relationship of neuroendocrine cells with other cell types.Keywords: Ascl1; lung; neuroendocrine; mouse; progenitor The murine respiratory system arises from the ventral foregut endoderm at around Embryonic Day (E) 9.5. The lung-bud epithelium invades the adjacent mesenchyme and starts branching to form a tree-like structure. The epithelium begins to differentiate during the pseudoglandular stage (E9.5-E16.5) (1). Multiple cell types contribute to both the structure and function of the lung. In the alveoli, Type II pneumocytes (AT2 cells) secrete surfactant, whereas Type I cells are responsible for gas exchange. In the airways, nonciliated secretory (Clara) cells have metabolic, anti-inflammatory, and anti-neoplastic properties, whereas ciliated cells eliminate excess mucus and harmful particles. In addition, the airway lining contains rare but important pulmonary neuroendocrine cells (PNECs) that may regulate breathing and contribute to carcinogenesis (2-4). PNECs occur as either solitary cells or clusters called neuroepithelial bodies (NEBs) (5). In developing lungs, PNECs begin to differentiate before other cells, but their histogenesis has remained elusive.Lung development is a complex process that requires mutual interactions between the mesoderm-derived mesenchyme and endoderm-derived epithelium. Both in vivo and in organ culture, a previous study demonstrated the early pseudoglandular stage of the lung as a dynamic structure, with smooth muscle and neural tissue in a prime position to influence growth and development (6). During embryonic lung development, intrinsic nerve ganglia function to innervate the airway smooth muscle (7). NEBs are extensively innervated, and may act as sensory airwa...

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Calcitonin driven v-Ha-ras induces multilineage pulmonary epithelial hyperplasias and neoplasms

Cited by 29 publications

References 60 publications

Expression profiling of primary non-small cell lung cancer for target identification

Expression profiling of primary non-small cell lung cancer for target identification

Atypical Adenomatous Hyperplasia of the Lung: A Probable Forerunner in the Development of Adenocarcinoma of the Lung

Multidirectional Differentiation of Achaete–Scute Homologue–1–Defined Progenitors in Lung Development and Injury Repair

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