Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado.
Eastern Colorado Veterans Affairs Medical Center, Aurora, Colorado.
Cancer Prev Res (Phila). 2018 Oct;11(10):643-654. doi: 10.1158/1940-6207.CAPR-18-0052. Epub 2018 Jul 25.
Lung cancer is the leading cause of cancer death worldwide and global burden could be reduced through targeted application of chemoprevention. The development of squamous lung carcinoma has been linked with persistent, high-grade bronchial dysplasia. Bronchial histology improved in former smokers in a chemoprevention trial with the prostacyclin analogue iloprost. Prostacyclin acts through peroxisome proliferator-activated receptor gamma (PPARγ) to reverse epithelial to mesenchymal transition and promote anticancer signaling. We hypothesized that the prostacyclin signaling pathway and EMT could provide response markers for prostacyclin chemoprevention of lung cancer. Human bronchial epithelial cells were treated with cigarette smoke condensate (CSC) or iloprost for 2 weeks, CSC for 16 weeks, or CSC for 4 weeks followed by 4 weeks of CSC and/or iloprost, and RNA was extracted. Wild-type or prostacyclin synthase transgenic mice were exposed to 1 week of cigarette smoke or one injection of urethane, and RNA was extracted from the lungs. We measured potential markers of prostacyclin and iloprost efficacy in these models. We identified a panel of markers altered by tobacco carcinogens and inversely affected by prostacyclin, including γ, These data introduce a panel of potential markers for monitoring interception of bronchial dysplasia progression during chemoprevention with prostacyclin. Chemoprevention is a promising approach to reduce lung cancer mortality in a high-risk population. Identifying markers for targeted use is critical for success in future clinical trials of prostacyclin for lung cancer chemoprevention. .
肺癌是全球癌症死亡的主要原因，通过有针对性地应用化学预防，全球负担可能会减轻。鳞状肺癌的发展与持续的、高级别的支气管异型增生有关。在一项使用前列环素类似物伊洛前列素的化学预防试验中，前吸烟者的支气管组织学得到改善。前列环素通过过氧化物酶体增殖物激活受体 γ（PPARγ）发挥作用，逆转上皮间质转化并促进抗癌信号。我们假设前列环素信号通路和 EMT 可以为前列环素预防肺癌提供反应标志物。用香烟烟雾冷凝物（CSC）或伊洛前列素处理人支气管上皮细胞 2 周，CSC 处理 16 周，或 CSC 处理 4 周，然后再用 CSC 和/或伊洛前列素处理 4 周，并提取 RNA。将野生型或前列环素合酶转基因小鼠暴露于 1 周的香烟烟雾或 1 次注射脲烷，然后从肺部提取 RNA。我们在这些模型中测量了潜在的前列环素和伊洛前列素疗效标志物。我们确定了一组由烟草致癌物改变并受前列环素反向影响的标志物，包括 γ。这些数据为监测化学预防过程中支气管异型增生进展提供了一组潜在的标志物。化学预防是降低高危人群肺癌死亡率的一种有前途的方法。确定用于靶向使用的标志物对于未来前列环素预防肺癌的临床试验的成功至关重要。
