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M. Edwards
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MINI 11 - Tobacco Control and Prevention (ID 108)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Prevention and Tobacco Control
- Presentations: 1
- Moderators:S.M. Janes, E. Stone, K.M. Cummings
- Coordinates: 9/07/2015, 16:45 - 18:15, 601+603
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MINI11.04 - A New Preclinical Model of Airway Progenitor Cells to Identify Responders to Iloprost-Mediated Chemoprevention (ID 1698)
16:55 - 17:00 | Author(s): M. Edwards
- Abstract
- Presentation
Background:
Lung cancer is the leading cause of cancer related deaths worldwide. The 5-year survival rate for this cancer is only 16%. Chemoprevention can improve prognosis in these patients. However, previous attempts at lung cancer chemoprevention that were soley based on epidemiological data were ineffective. Squamous cell lung cancer develops through a series of bronchial lesions or dysplasia. Persistent dysplasia harbors similar genetic changes as the tumor and has significantly higher chance of progression. Thus, bronchial dysplasia is a risk biomarker for SCC and improvement in dysplasia grade can be used as an outcome for chemoprevention trials. The long-acting prostacyclin analogue, iloprost is the only drug that has improved dysplasia in former smokers (p = 0.006). Despite this positive outcome we have little insight into the mechanisms of iloprost function. Understanding these mechanisms would be essential to identify people who have the highest chance to benefit from iloprost treatment. We propose that this endeavor will require a preclinical model that recapitulates the human disease and is amenable to mechanistic studies.
Methods:
Airway progenitor cells are critical for the maintenance of normal airways, because of their ability to self-renew (i.e. replicate) and differentiate into all cell-types of the airway (i.e. multipotentiality). Together these properties allow progenitors to return injured tissue to normal structure and function. In dysplasia, normal bronchial epithelium is changed into one that contains increased numbers of basal cells and lacks ciliated cells. These findings led to our hypothesis that ‘airway progenitors are malfunctioning in dysplasia’. Previously we showed that Keratin (K) 5/p63-expressing basal cells are the multipotential progenitors of the airway epithelium. During in vitro culture these cells form a unique 3-deimensional structure called the rim clone, which allows them to be distinguished from non-progenitors. To investigate a role of epithelial progenitors in dysplasia, we have collected bronchial biopsies from high-risk smokers and purified rim clone forming basal progenitor cells.
Results:
We demonstrate that both self-renewal and multipotentiality of progenitors is significantly (p < 0.001 for both) decreased in dysplasia. During differentiation in vitro at the air-liquid interface, progenitors from normal biopsies generated a normal epithelium. In contrast, progenitors from dysplasia made a squamous epithelium containing only basal cells and lacking ciliated cells. Mutational analyses of paired samples from epithelial brushings and biopsy-derived progenitors identified the same somatic mutations in p53, Notch 1, Notch 3, Survivin and FGFR1. Thus, epithelial progenitor culture reflects the histologic and genetic changes of dysplasia and therefore can be used as a personalized, preclinical model. A proof of concept study where dysplastic progenitor cells were treated with iloprost resulted in decreased dysplasia in 2 out of 3 cases.
Conclusion:
Thus our data indicate that progenitor cell cultures from a patient’s dysplasia may be used to identify responders versus non-responders to iloprost, as well as other chemopreventives. Future studies could focus on identifying downstream mechanisms via which iloprost exerts its beneficial effect.
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MINI 23 - Lung Cancer Risk: Genetic Susceptibility and Airway Biology (ID 135)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Screening and Early Detection
- Presentations: 1
- Moderators:P.E. Postmus, R. Young
- Coordinates: 9/08/2015, 16:45 - 18:15, 401-404
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MINI23.10 - Subtraction of Allelic Fractions (Delta-θ): A Sensitive Metric to Detect Chromosomal Alterations in Heterogeneous Premalignant Specimens (ID 2434)
17:35 - 17:40 | Author(s): M. Edwards
- Abstract
- Presentation
Background:
Lung squamous carcinoma is believed to arise from premalignant bronchial epithelial dysplasia, which demonstrates progressive histologic changes leading up to invasive cancer. However, only a small subset of these lesions progress to carcinoma. Recent studies have shown that somatic chromosomal alterations (SCAs) status is a better biomarker than premalignant histology alone. Single-nucleotide polymorphism microarray (SNP array) has been frequently used to delineate these genomic alterations across the whole genome. However, the cellular heterogeneity, from clinical samples such as endobronchial specimens, is a basic obstacle to perform sensitive and accurate detection of SCAs.
Methods:
We used: 1) a lung cancer cell line (NCI-H1395) and its matched lymphoblastoid (NCI-BL1395) cell line; 2) frozen lung tissues containing different percentage of invasive cancer cells surgically resected from a patient; and 3) biopsies and brushings obtained at the visually concerning areas during bronchoscopy. The histology of the clinical samples were graded by the study pathologist. Genomic DNA was isolated from each sample, quantified, and labeled for Illumina SNP array (HumanOmni 2.5-Quad BeadChip). Data analysis and visualizations were performed using Partek Genomic Suite 6.6 software.
Results:
Our study focused on the detection of SCAs by the comparison of genomic DNAs from cancer/premalignant cells (subject) to blood/normal cells (reference) from the same individual. We tested a B allele frequency metric, the subtraction of allelic fractions (delta-θ), on a standardized mixture of genomic DNAs from a lung cancer cell line and its matched lymphoblastoid cell line. Delta-θ proved to be a sensitive parameter to clearly delineate SCAs present in the tumor cell line even with a large proportion of normal cells (up to 90%). To explore the utility of using delta-θ for heterogeneous samples, we used clinical lung cancer specimens with known cancer cell content. In comparison to the other publicly available analytical metrics/algorithms (conventional Log R Ratio plot, mirrored B Allele Frequency plot, and GAP algorithm), delta-θ performed as well or better (with lower computational power needed), and enabled the detection of SCAs even in highly heterogeneous clinical samples (<30% tumor cell content). In addition, we completed a study using a number of bronchial biopsies and brushings with histologic grade ranging from normal to squamous cell carcinoma. SCAs were rarely detected in those of low to mild dysplasia, while they were detected in approximately 25% of moderate or severe dysplasia, and in all carcinoma in situ (CIS) and squamous cell carcinoma specimens. Longitudinal, repeated samplings from a high risk patient who persistently showed high grade dysplasia across the bronchus, revealed that delta-θ could identify SCAs continuously across the whole genome. The fact this individual had highly overlapping SCAs between different bronchial locations indicates genomic field cancerization may occur, along with the histological field effect in premalignant epithelium.
Conclusion:
In SNP microarray studies, delta-θ is a highly sensitive metric for detecting SCAs even in heterogeneous dysplastic bronchial specimens. SNP array may be a powerful tool to understand premalignant genetic alterations and field cancerization.
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