Oweida Ayman, Sabri Siham, Al-Rabea Areej, Ebrahimi Mojgan, Ruo Russel, Fraser Richard, Seuntjens Jan, Abdulkarim Bassam
Department of Radiation Oncology, University of Colorado Denver, Aurora, Colorado 80045, USA.
Division of Radiation Oncology, McGill University Health Center, Montreal, Quebec H4A 3J1, Canada.
Oncotarget. 2017 Nov 28;9(2):1630-1640. doi: 10.18632/oncotarget.22727. eCollection 2018 Jan 5.
Stereotactic ablative radiotherapy (SABR) is the main treatment for inoperable early-stage non-small cell lung cancer (NSCLC). Despite the widespread use of SABR, the biological determinants of response to SABR remain poorly investigated. We developed an orthotopic NSCLC animal model to study the response to clinically-relevant doses of SABR. Image-guided intra-thoracic injection of NSCLC cells was performed in the right lung of nude rats. A highly conformal dose of 34 Gy was delivered in a single fraction using clinical photon energies. Animals were sacrificed 10-60 days post treatment. Lung tumors were assessed for tumor differentiation, proliferation and invasiveness. An analysis of 770 cancer-related genes was performed on tumor-derived cell lines from treated animals at early and late time points after SABR. The majority of animals receiving SABR demonstrated complete response (67%), while 33% demonstrated local failure. 50% of animals with complete response failed distantly. Analysis of cancer-related genes revealed significant differences between tumors treated with SABR and untreated tumors. SABR significantly modulated expression of genes involved in adhesion, migration and angiogenesis. In particular, interleukin-8 (IL8) which plays a critical role in promoting tumor invasion was found to be secreted at high levels after SABR. invasion assays confirmed SABR-induced invasion and demonstrated induction of IL-8 secretion in multiple NSCLC cell lines. Our findings underscore the importance of developing targeted therapies that can circumvent the pro-invasive effects of SABR in NSCLC.
立体定向消融放疗（SABR）是不可手术的早期非小细胞肺癌（NSCLC）的主要治疗方法。尽管SABR已广泛应用，但对SABR反应的生物学决定因素仍研究不足。我们建立了一种原位NSCLC动物模型，以研究对临床相关剂量SABR的反应。在裸鼠右肺中进行图像引导下的NSCLC细胞胸腔内注射。使用临床光子能量单次给予34 Gy的高度适形剂量。治疗后10 - 60天处死动物。评估肺肿瘤的肿瘤分化、增殖和侵袭性。对SABR后早期和晚期时间点来自治疗动物的肿瘤衍生细胞系进行770个癌症相关基因的分析。大多数接受SABR的动物表现出完全缓解（67%），而33%表现出局部失败。50%完全缓解的动物出现远处失败。癌症相关基因分析显示，接受SABR治疗的肿瘤与未治疗的肿瘤之间存在显著差异。SABR显著调节参与黏附、迁移和血管生成的基因表达。特别是，在促进肿瘤侵袭中起关键作用的白细胞介素-8（IL8）在SABR后被发现高水平分泌。侵袭试验证实了SABR诱导的侵袭，并证明在多个NSCLC细胞系中诱导了IL-8分泌。我们的研究结果强调了开发靶向治疗以规避SABR在NSCLC中的促侵袭作用的重要性。
