食管癌放疗过程中肿瘤干细胞加速再增殖与乏氧微环境关系及PET分子影像研究

Radiotherapy is main modality for esophageal cancer, but the outcome remains unsatisfying. Accelerated repopulation of tumor cells during radiotherapy is believed to contribute to radioresistance and is an important cause for treatment failure. In essence the mechanism of tumor accelerated repopulation involves the accelerated proliferation of clonogenic cancer stem cells (CSCs). Our studies found that PET molecular imaging could detect tumor accelerated repopulation and hypoxia during radiotherapy in esophageal cancer. It is hypothesized that detecting CSCs changing during treatment by PET molecular imaging together with molecular stem cell markers will be helpful to reveal biological mechanism of radio-resistance and further guide individualized radiotherapy. This study using tumor model and clinical data is proposed to: (1) define the relationship between accelerated repopulation and hypoxia microenvironment measured by PET molecular imaging based on pathology; (2) identify whether PET molecular imaging could detect accelerated repopulation of CSCs during radiotherapy compared with fluorescence-based optical imaging and immunohistochemistry imaging; (3) analyze the relationship between radio-resistance and biological niches including accelerated repopulation and hypoxia detected by PET molecular imaging; explore the potential role of PET molecular imaging in defining CSCs biological target. This study will reveal the biological niches including accelerated repopulation and hypoxia correlated with radio-resistance and provide a molecular imaging tool for detecting CSCs dynamically and defining biological target of CSCs during radiotherapy in esophageal cancer.

放疗是食管癌的主要治疗手段，但疗效仍不令人满意。肿瘤加速再增殖是导致放疗耐受的重要生物学因素，其本质是放疗过程中聚集在乏氧微环境下的肿瘤干细胞发生了氧合、加速增殖。我们前期研究发现，PET分子影像是监测肿瘤加速再增殖及乏氧的理想手段，于是推测可以利用PET分子影像结合肿瘤干细胞标志物检测肿瘤干细胞动态变化。本项目拟通过动物实验和临床研究，（1）与病理标本比对，确定PET分子影像反映的加速再增殖与乏氧微环境之间的关系（2）以肿瘤干细胞生物荧光成像和免疫组化比对，确定PET分子影像能否监测肿瘤干细胞加速再增殖（3）比较PET分子影像检测的肿瘤干细胞乏氧微环境和加速再增殖生物学壁龛与放疗耐受的关系，探讨应用PET分子影像构建肿瘤干细胞生物学靶区的可能性。本研究将揭示食管癌放疗耐受与肿瘤干细胞加速再增殖、乏氧微环境之间的关系，并为动态监测肿瘤干细胞变化和构建肿瘤干细胞生物学靶区提供分子影像手段。

放疗是食管癌的主要治疗手段，但疗效仍不令人满意，放射性肺炎是疗效不佳的根源之一。18F-FDG PET可以量化和预测放射性肺炎严重程度，18F-FDG PET可以检测和量化放射性肺炎患者报告症状，治疗前或治疗中PET的照射肺FDG 摄取值能预测医生评价的放射性肺炎。通过送检放射性肺炎动物模型的照射肺和健侧肺组织，进行肺组织定量蛋白质组学分析。差异蛋白筛选及生物学信息分析发现与糖酵解通路相关蛋白数量富集显著，其中以PKM2蛋白上调最明显。提示PKM2介导糖代谢重编程可能参与放射性肺炎的发生。