β-榄香烯对放疗诱导的肺癌血管形成的作用和分子机制研究

The management of inhibiting tumor vessels is an effective method to enhance radiotherapy effect toward lung cancer. Radiation can completely abrogate local tumor angiogenesis, thus vasculogenesis may become the prime way to rebuilt new vasculature for residual and recurrent tumors. But the underlying mechanism is far from clear and merits further investigation. Some studies have recently shown lung cancer cells and tumor associated macrophages (TAMs) may promote vesculogenesis through a possible self-perpetuating positive loop between TLR4 /NF-κB and HIF-1α activated by Prx-1 that results in the recruitment and M2 phenotype polarization of TAM under tumor hypoxia. Our previous study have shown the radiosensibilization of β-elemene is related with inhibiting vessels of lung cancer， and HIF-1α and Prx-1 are molecular targets. So the present study plans to explore the synergy effect of β-elemene with radiation toward vasculogenesis, and the relationship with the positive loop between TLR4 /NF-ΚB and HIF-1α activated by Prx-1 under hypoxic circumstances induced by radiotherapy. We try to clarify whether this molecular loop is the underlying mechanism by which to promote lung cancer vasculogenesis induced by radiation and find critical targets. The aim of this research is to provid theoretical foundation for developing anti-vessels targeted therapy and to suggest β-elemene as anti-vascologenesis drug to enhance radiation effect.

抗肿瘤血管药协同放疗是提高肺癌放疗疗效的有效手段。放疗虽然可直接破坏肿瘤血管新生，但依赖骨髓来源肿瘤相关巨噬细胞（TAM）募集的血管形成，却成为放疗后残存、复发肿瘤重构血管的途径，其作用机制值得进一步探讨。新近研究表明在乏氧环境下，肺癌细胞和TAM细胞可能通过Prx-1激活的TLR4/NF-κB与HIF-1α间正反馈分子环路，诱导TAM的募集和M2表型的转化，促进肿瘤生成新的血管。我们前期也发现中药β-榄香烯对肺癌的放射增敏作用与抗肺癌血管生成有关，且增敏的靶点为HIF-1α、Prx-1。因此本课题旨在通过在放疗诱导的乏氧环境下，检测β-榄香烯和放疗对肺癌血管形成的作用以及Prx-1激活的TLR4/NF-κB与HIF-1α间正反馈分子环路影响，明确该正反馈分子环路是放疗诱导肺癌血管形成的重要机制和主要靶点，以期为开发抗血管靶向药物和中药β-榄香烯作为抗血管生成药物提高肺癌疗效提供理论依据。

肺癌的发病率和病死率目前已居恶性肿瘤之首，尽管近些年来肺癌的手术、化疗、 放疗、靶向治疗、生物免疫治疗等各种治疗方法有了很大的进步，但是总的5年生存率仍小于15%。肿瘤的复发和转移是导致肺癌患者死亡的主要原因。目前研究认为，血管生成是原发性肿瘤的生长、繁殖和转移的关键环节。因此深入研究肿瘤血管形成的分子机制并寻找临床有效药物，对于提高放疗疗效具有重要科学意义和临床价值。申请人及其课题组研究发现放疗能够诱导M2型巨噬细胞的浸润，释放炎性因子，促进新生血管生产，增加肺癌细胞转移及侵袭能力。放射破坏肿瘤组织中的血管，造成乏氧加重。项目研究证实放疗诱导的乏氧微环境下，肺癌细胞存在依赖Prx-1激活NF-κB及HIF-1α之间信号调节通路，通过促进MCP-1等表达，诱导巨噬细胞的募集，促进肿瘤生成新的血管。β-榄香烯可通过抑制Prx-1、HIF-1α表达，干预这条分子途径，对放疗诱导的肿瘤血管形成发挥抑制作用。本项课题研究证实肺癌细胞、肿瘤相关巨噬细胞是放疗诱导血管形成的主要细胞，两细胞存在的Prx-1/NF-κB与HIF-1α之间正反馈分子环路，是促进血管形成的重要分子机制，为肺癌治疗提供更多潜在靶点。