大分割放疗(HFRT)显著提高早期非小细胞肺癌的局控率,但转移仍是患者死亡首因。改善乏氧或靶向杀伤乏氧肿瘤细胞可降低HFRT后转移的发生,提示乏氧在其中起重要作用。我们发现HFRT后早期肿瘤微循环血流降低、乏氧增加、激活乏氧应答,推测乏氧诱导肿瘤细胞乏氧应答,上调转移基因,促进转移。拟采用已建立的稳定表达荧光素酶报告基因(M38-Luc)和乏氧应答双报告基因(9HRE-TK/eGFP)的肺癌模型,PET显像监测肿瘤乏氧和乏氧应答,荧光素酶显像监测转移,通过①HFRT联合高氧/低氧吸入改变肿瘤氧供，或硼替佐米阻断乏氧应答，明确乏氧和乏氧应答与转移的因果关系;②流式技术分选HFRT后乏氧肿瘤细胞,行转移功能基因组芯片分析、筛选乏氧调控关键转移基因(DG);③体内外联合应用DG拮抗剂,探讨靶向阻断DG、降低转移的可能性。本项目将为揭示HFRT后转移发生的机制、降低转移提高整体疗效提供科学依据。

Hypofractionated radiotherapy (HFRT) significantly improved the local control in early-stage non-small-cell lung cancer. However, metastases remain the first cause of death. It is indicated that hypoxia play an important role in metastases after HFRT since distant metastases could be decreased by improving tumor oxygenation or selectively killing hypoxic cancer cells. Our study found that HFRT decreased tumor blood perfusion, increased tumor hypoxia, and then activated tumor hypoxia response shortly after treatments. We hypothesized that hypoxia promote metastases through hypoxia response up-regulating metastasis related genes. An established novel lung cancer model containing stably transfected Luciferase reporter gene (M38-Luc) and hypoxia response dual reporter gene (9HRE-TK/eGFP) will be used in this study. Tumor hypoxia and hypoxia response will be monitored using PET imaging with 18F-FETNIM and 18F-FHBG (TK substrate), respectively, and tumor growth and metastases by bioluminescence imaging. This study is proposed to: 1) identify the causal effect of tumor hypoxia and tumor hypoxia response on distant metastases after HFRT by oxygen intervention (95% or 10% O2 breathing), and proteasome inhibitor Bortezomib which inhibits hypoxia response, respectively; 2) screen the hypoxia regulated dominant metastasis genes (DG) using flow cytometry hypoxic cell sorting and functional gene-chip analysis; 3) explore the potential of decreasing metastases by combining DG inhibitors with HFRT. This study will reveal the metastatic mechanism after HFRT from the view of tumor hypoxia and hypoxia response, and provide the scientific evidence for reducing metastases and improve outcome for HFRT.