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M. Tennis
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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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MINI11.02 - Frizzled9 as a Predictor of Response to Iloprost Chemoprevention of Lung Cancer (ID 2397)
16:45 - 18:15 | Author(s): M. Tennis
- Abstract
- Presentation
Background:
Lung cancer remains the leading cause of cancer death in the United States and chemoprevention offers an appealing area of investigation in the face of limited therapeutic success. Improvement in endobronchial histology was recently demonstrated in former smokers after oral iloprost treatment. Of the 48 patients who received iloprost in the chemoprevention trial, 23 had regressive histology and 25 had stable or progressive histology. Identifying markers that predict which patients will respond to treatment will help refine target populations for future trials and clinical applications. In vitro studies of NSCLC indicate that iloprost, a prostacyclin analogue, acts through the G-protein coupled receptor Frizzled 9 (Fzd9) instead of the prostacyclin receptor. We hypothesize that Fzd9 expression status predicts response to iloprost chemoprevention and that current smokers may not respond to iloprost treatment due to carcinogen-induced decreases in Fzd9 expression. Prostacyclin may also induce expression of Fzd9, leading to increased anti-tumor signaling.
Methods:
Fzd9 expression was measured by quantitative real-time PCR in RNA extracted from mouse and human tissues, cultured dysplastic cell lines, and cultured human bronchial epithelial cells (HBEC). In the urethane model, FVB wild type and transgenic mice were exposed to a single dose of urethane and sacrificed after 20 weeks. In the smoking model, FVB wild type and transgenic mice were sacrificed after one week of cigarette smoke exposure. Human matched tumor and normal tissue and dysplastic cell lines were acquired from the University of Colorado SPORE in Lung Cancer Tissue Bank. HBEC were exposed to 5ug/ml cigarette smoke condensate and 10uM iloprost in culture media.
Results:
Human lung tumors demonstrated reduced Fzd9 mRNA expression compared to matched normal lung tissue. Fzd9 expression is also decreased in human primary dysplastic cell lines, suggesting that loss of Fzd9 expression occurs early in early lung lesions. In a urethane mouse model of lung cancer, Fzd9 mRNA expression is reduced in lung tumors compared to matched, uninvolved lung tissue. Tumors from urethane exposed prostacyclin synthase overexpressing (PGIStg) mice have higher Fzd9 expression compared to tumors from wild type mice. In a one-week smoking model, Fzd9 expression is decreased in lung from wild type smoked mice but higher in PGIStg smoked mice. In HBEC exposed to cigarette smoke, Fzd9 expression decreases and remains low with continued exposure from 1 to 28 weeks. After two weeks of exposure to iloprost alone, HBEC cells demonstrated increased Fzd9 expression.
Conclusion:
These initial studies suggest that Fzd9 expression is lost lung epithelial cells with early smoking-induced damage. Fzd9 expression will be measured in baseline and follow up biopsy tissues from the iloprost clinical trial. This study has the potential to improve iloprost lung cancer chemoprevention by allowing future trials to more effectively target high-risk patients and by providing a clinical biomarker for identification of chemoprevention candidates.
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P2.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 234)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.04-062 - Temporal Programming of Murine Pulmonary Macrophages in N-Nitroso-Tris-(2-Chloroethyl) Urea (NTCU)-Induced Squamous Dysplasia (ID 2955)
09:30 - 17:00 | Author(s): M. Tennis
- Abstract
Background:
Continuous topical application of N-Nitroso-tris-(2-chloroethyl)urea (NTCU) twice per week for 32 weeks causes the development of squamous dysplasia and lung carcinoma (SCC) in certain strains of inbred mice including A/J and FVB mice. In A/J mice, short term/high dose topical application of NTCU induces higher grade squamous lung lesions at earlier times with less toxicity than the 32 week, continuous dosing model. In lung adenocarcinoma, alveolar macrophages become alternatively programmed shortly after carcinogen exposure, before lung lesions are detected indicating that inflammation may be important in lesion development. Herein we examine whether short term/high dose NTCU exposure produces squamous dysplastic lesions in FVB mice. In addition, we characterize macrophage programming as a function of time during lesion development.
Methods:
FVB/N mice were treated with 20mM NTCU twice/week for 2, 4, 8, or 32 weeks and lungs were harvested at 16, 20, 24, 28, and 32 weeks after the initial application. The appearance of squamous lesions was monitored by stereology at the later time point and by the appearance of cytokeratin 5-positive bronchial cells at the earlier time points. Inflammatory cell content was determined by flow cytometry at the 16, 20, 24, and 32 week time in the mice continuously exposed to NTCU and compared to vehicle control. Macrophage programming was assessed by immunofluorescent detection iNOS or arginase I expression .
Results:
Squamous dysplasia appeared in the tracheas of NTCU-treated mice after 16 continual weeks of NTCU exposure, but lung dysplasia was not evident until 8-10 weeks later. The appearance of cytokeratin 5 positive cells in the airways preceded the appearance of these lesions. In mice treated with 8 weeks of NTCU, cytokeratin 5 positive cells in the airways appeared at 24 weeks and dysplastic lesions were also detected. Alveolar macrophage numbers also increased at the 24 week time point in these mice. Data from 28 and 32 week time points is currently being analyzed. Alveolar macrophages displayed little change in iNOS or arginase I staining through 20 weeks, however there were isolated iNOS[+] and arginase I[+] macrophages at 24 weeks. There were also weakly activated macrophages present in mice treated with NTCU continuously for 32 weeks although alveolar macrophage numbers did not increase significantly.
Conclusion:
The short term/high dose NTCU treatment regimen is less toxic and produces dysplastic lesions at times similar to those in continuous exposure groups. Alveolar macrophage numbers also increase as a function of time in the short term/high dose model whereas there is less reproducibility of this increase in the continuous dosing model. Changes in alveolar macrophage programming occur during dysplastic lesion development, but not to the same extent as that seen in progression of adenomas and adenocarcinomas.
