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      Adult lung stem cells and their contribution to lung tumourigenesis

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          Abstract

          The isolation and characterization of lung stem and progenitor cells represent an important step towards the understanding of lung repair after injury, lung disease pathogenesis and the identification of the target cells of transformation in lung carcinogenesis. Different approaches using prospective isolation of progenitor cells by flow cytometry or lineage-tracing experiments in mouse models of lung injury have led to the identification of distinct progenitor subpopulations in different morphological regions of the adult lung. Genetically defined mouse models of lung cancer are offering new perspectives on the cells of origin of different subtypes of lung cancer. These mouse models pave the way to further investigate human lung progenitor cells at the origin of lung cancers, as well as to define the nature of the lung cancer stem cells. It will be critical to establish the link between oncogenic driver mutations recently discovered in lung cancers, target cells of transformation and subtypes of lung cancers to enable better stratification of patients for improved therapeutic strategies.

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          Most cited references90

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          Classification of human lung carcinomas by mRNA expression profiling reveals distinct adenocarcinoma subclasses.

          We have generated a molecular taxonomy of lung carcinoma, the leading cause of cancer death in the United States and worldwide. Using oligonucleotide microarrays, we analyzed mRNA expression levels corresponding to 12,600 transcript sequences in 186 lung tumor samples, including 139 adenocarcinomas resected from the lung. Hierarchical and probabilistic clustering of expression data defined distinct subclasses of lung adenocarcinoma. Among these were tumors with high relative expression of neuroendocrine genes and of type II pneumocyte genes, respectively. Retrospective analysis revealed a less favorable outcome for the adenocarcinomas with neuroendocrine gene expression. The diagnostic potential of expression profiling is emphasized by its ability to discriminate primary lung adenocarcinomas from metastases of extra-pulmonary origin. These results suggest that integration of expression profile data with clinical parameters could aid in diagnosis of lung cancer patients.
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            Basal cells as stem cells of the mouse trachea and human airway epithelium.

            The pseudostratified epithelium of the mouse trachea and human airways contains a population of basal cells expressing Trp-63 (p63) and cytokeratins 5 (Krt5) and Krt14. Using a KRT5-CreER(T2) transgenic mouse line for lineage tracing, we show that basal cells generate differentiated cells during postnatal growth and in the adult during both steady state and epithelial repair. We have fractionated mouse basal cells by FACS and identified 627 genes preferentially expressed in a basal subpopulation vs. non-BCs. Analysis reveals potential mechanisms regulating basal cells and allows comparison with other epithelial stem cells. To study basal cell behaviors, we describe a simple in vitro clonal sphere-forming assay in which mouse basal cells self-renew and generate luminal cells, including differentiated ciliated cells, in the absence of stroma. The transcriptional profile identified 2 cell-surface markers, ITGA6 and NGFR, which can be used in combination to purify human lung basal cells by FACS. Like those from the mouse trachea, human airway basal cells both self-renew and generate luminal daughters in the sphere-forming assay.
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              Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK.

              The EML4-ALK fusion oncogene represents a novel molecular target in a small subset of non-small-cell lung cancers (NSCLC). To aid in identification and treatment of these patients, we examined the clinical characteristics and treatment outcomes of patients who had NSCLC with and without EML4-ALK. Patients with NSCLC were selected for genetic screening on the basis of two or more of the following characteristics: female sex, Asian ethnicity, never/light smoking history, and adenocarcinoma histology. EML4-ALK was identified by using fluorescent in situ hybridization for ALK rearrangements and was confirmed by immunohistochemistry for ALK expression. EGFR and KRAS mutations were determined by DNA sequencing. Of 141 tumors screened, 19 (13%) were EML4-ALK mutant, 31 (22%) were EGFR mutant, and 91 (65%) were wild type (WT/WT) for both ALK and EGFR. Compared with the EGFR mutant and WT/WT cohorts, patients with EML4-ALK mutant tumors were significantly younger (P < .001 and P = .005) and were more likely to be men (P = .036 and P = .039). Patients with EML4-ALK-positive tumors, like patients who harbored EGFR mutations, also were more likely to be never/light smokers compared with patients in the WT/WT cohort (P < .001). Eighteen of the 19 EML4-ALK tumors were adenocarcinomas, predominantly the signet ring cell subtype. Among patients with metastatic disease, EML4-ALK positivity was associated with resistance to EGFR tyrosine kinase inhibitors (TKIs). Patients in the EML4-ALK cohort and the WT/WT cohort showed similar response rates to platinum-based combination chemotherapy and no difference in overall survival. EML4-ALK defines a molecular subset of NSCLC with distinct clinical characteristics. Patients who harbor this mutation do not benefit from EGFR TKIs and should be directed to trials of ALK-targeted agents.
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                Author and article information

                Journal
                Open Biol
                Open Biol
                RSOB
                royopenbio
                Open Biology
                The Royal Society
                2046-2441
                August 2012
                August 2012
                : 2
                : 8
                : 120094
                Affiliations
                [1 ]ACRF Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research , Parkville, Victoria, Australia
                [2 ]Department of Medical Biology, The University of Melbourne , Parkville, Victoria, Australia
                Author notes
                Article
                rsob120094
                10.1098/rsob.120094
                3438537
                22977734
                75c56cd0-6010-41e7-827f-388a1d797b08

                © 2012 The Authors. Published by the Royal Society under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0/, which permits unrestricted use, provided the original author and source are credited.

                History
                : 16 May 2012
                : 23 July 2012
                Categories
                1001
                33
                197
                Review
                Review Article
                Custom metadata
                August 2012

                Life sciences
                lung stem cells,cell of origin of lung cancer,lung cancer,lung disease and repair,cancer stem cells

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