Sompel Kayla, Dwyer-Nield Lori D, Smith Alex J, Elango Alamelu, Backos Don S, Zhang Bicheng, Gross James, Ternyak Kristina, Matsuda Jennifer L, Kopf Katrina, Keith Robert L, Tennis Meredith A
Division of Pulmonary Sciences and Critical Care Medicine, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
Skaggs School of Pharmacy, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
iScience. 2022 May 23;25(6):104442. doi: 10.1016/j.isci.2022.104442. eCollection 2022 Jun 17.
Prevention of premalignant lesion progression is a promising approach to reducing lung cancer burden in high-risk populations. Substantial preclinical and clinical evidence has demonstrated efficacy of the prostacyclin analogue iloprost for lung cancer chemoprevention. Iloprost activates peroxisome proliferator-activated receptor gamma (PPARG) to initiate chemopreventive signaling and , which requires the transmembrane receptor Frizzled (FZD). We hypothesized a mouse would not be protected by iloprost in a lung cancer model. mice were treated with inhaled iloprost in a urethane model of lung adenoma. We found that mice treated with iloprost were not protected from adenoma development compared to wild-type mice nor did they demonstrate increased activation of iloprost signaling pathways. Our results established that iloprost requires FZD for lung cancer chemoprevention. This work represents a critical advancement in defining iloprost's chemopreventive mechanisms and identifies a potential response marker for future clinical trials.
预防癌前病变进展是减轻高危人群肺癌负担的一种有前景的方法。大量临床前和临床证据表明，前列环素类似物伊洛前列素在肺癌化学预防方面具有疗效。伊洛前列素激活过氧化物酶体增殖物激活受体γ（PPARG）以启动化学预防信号传导，这需要跨膜受体卷曲蛋白（FZD）。我们假设在肺癌模型中，一种小鼠不会受到伊洛前列素的保护。在肺腺瘤的氨基甲酸乙酯模型中，对小鼠进行吸入伊洛前列素治疗。我们发现，与野生型小鼠相比，接受伊洛前列素治疗的小鼠并未免受腺瘤发展的影响，它们也未表现出伊洛前列素信号通路的激活增加。我们的结果表明，伊洛前列素在肺癌化学预防中需要FZD。这项工作代表了在确定伊洛前列素化学预防机制方面的一项关键进展，并确定了未来临床试验的潜在反应标志物。
