基于多模态MRI的直肠癌放疗抵抗早期预测及其机制研究

Radiotherapy is the main treatment approach of locally advanced rectal cancer. Radiotherapy resistance is an important factor affecting the curative efficacy. Tumor hypoxia microenvironment promoted angiogenesis and EMT and hence, play an important role in radio-resistance. However, it was lack of effective indicator to monitor hypoxia microenvironment and predict the radiotherapy resistance. The multi-modal MRI was used to observe the imaging features of the rectal cancer. It was showed that the quantitative parameters of DCE-MRI and DKI correlated with the characteristics of tumor microcirculation environment and the spatial heterogeneity, respectively. As such, we propose a hypothesis that multi-modal MRI quantitative parameters can indirectly reflect the tumor hypoxia microenvironment by macroscopically monitoring tumor angiogenesis and cell EMT in the course of radiotherapy. The MRI quantitative parameters are expected to become valid indicators for early prediction of radio-resistance. With this hypothesis, we constructed nude mice tumor radiotherapy model with both positive and negative regulation of tumor hypoxic microenvironment. The DCE-MRI and DKI are used to analyze hypoxia microenvironment changes and to explore corresponding changes of MRI quantitative parameters. Combined with molecular pathological indicators, the pathological mechanism of the MRI quantitative parameters to predict radiation resistance in rectal cancer are clarified, providing a theoretical basis for clinical individualized treatment.

放疗是局部进展期直肠癌的主要治疗手段，放疗抵抗是影响疗效的重要因素，肿瘤缺氧微环境促进新生血管生成及细胞上皮-间质转化（EMT）是放疗抵抗的重要原因，但是目前缺乏用于监测缺氧微环境进而早期预测放疗抵抗的有效指标。课题组前期用多模态MRI观察直肠癌影像学特征，发现DCE-MRI定量参数与肿瘤微循环特征相关，DKI定量参数能反映肿瘤空间结构异质性。据此我们提出假说：多模态MRI定量参数可通过宏观监测放疗过程中肿瘤新生血管生成及肿瘤细胞EMT，间接反映肿瘤缺氧微环境特征，可作为有效指标用于早期预测放疗抵抗。为此，我们构建裸鼠成瘤放疗模型，从正反两方面调控缺氧微环境，利用DCE-MRI及DKI定量分析直肠癌放疗过程中缺氧微环境变化，探索相应的MRI定量参数变化规律，结合分子病理学指标，阐明MRI定量参数预测直肠癌放疗抵抗的病理学机制，为临床个体化治疗提供理论依据。

放疗抵抗是影响局部进展期直肠癌治疗疗效的重要因素，早期预测放疗抵抗可以为直肠癌个体化治疗提供重要信息，但是目前缺乏有效指标。课题组运用学科交叉的方法，综合多模态MRI成像/后处理与分子生物学技术，拟探讨并阐明MRI定量参数早期预测直肠癌放疗抵抗的病理学机制。研究结果：（1）通过多模态MRI观察直肠癌影像学特征间接反映肿瘤缺氧微环境，以及肿瘤缺氧微环境促进新生血管生成及细胞上皮-间质转化（EMT）这一肿瘤微环境改变。（2）多模态MRI定量参数能反应直肠癌放疗抵抗，机制解释是MRI功能成像能够反映肿瘤内部缺氧状态。（3）增加了临床患者的一部分数据，对于课题开展和后续研究是一个推进，明确多模态MRI哪些定量参数能够反映直肠癌放疗抵抗，探讨最佳参数组合模式。综上，本课题研究结果为多模态MRI定量参数运用于临床提供依据。