Group of Radiation Biology and Tumor Physiology, Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
Group of Radiation Biology and Tumor Physiology, Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
Int J Radiat Oncol Biol Phys. 2019 Jul 1;104(3):666-676. doi: 10.1016/j.ijrobp.2019.03.002. Epub 2019 Mar 8.
This study had a dual purpose: to investigate (1) whether bevacizumab can change the microvasculature and oxygenation of cervical carcinomas and (2) whether any changes can be detected with dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI).
Two patient-derived xenograft models of cervical cancer (BK-12 and HL-16) were included in the study. Immunostained histologic preparations from untreated and bevacizumab-treated tumors were analyzed with respect to microvascular density, vessel pericyte coverage, and tumor hypoxia using CD31, α-SMA, and pimonidazole as markers, respectively. DCE-MRI was performed at 7.05 T, and parametric images of K and v were derived from the data using the Tofts pharmacokinetic model.
The tumors of both models showed decreased microvascular density, increased vessel pericyte coverage, and increased vessel maturation after bevacizumab treatment. Bevacizumab-treated tumors were more hypoxic and had lower K values than untreated tumors in the BK-12 model, whereas bevacizumab-treated and untreated HL-16 tumors had similar hypoxic fractions and similar K values. Significant correlations were found between median K and hypoxic fraction, and the data for untreated and bevacizumab-treated tumors were well fitted by the same curve in both tumor models.
Bevacizumab-treated tumors show less abnormal microvessels than untreated tumors do, but because of treatment-induced vessel pruning, the overall function of the microvasculature might be impaired after bevacizumab treatment, resulting in increased tumor hypoxia. DCE-MRI has great potential for monitoring bevacizumab-induced changes in tumor hypoxia in cervical carcinoma.
本研究具有双重目的：（1）研究贝伐单抗是否能改变宫颈癌的微血管和氧合作用；（2）是否可以通过动态对比增强磁共振成像（DCE-MRI）检测到任何变化。
本研究纳入了两个宫颈癌患者来源的异种移植模型（BK-12 和 HL-16）。使用 CD31、α-SMA 和 pimonidazole 分别作为标记物，对未经处理和贝伐单抗处理的肿瘤的免疫组化组织学标本进行分析，以评估微血管密度、血管周细胞覆盖率和肿瘤缺氧情况。在 7.05T 下进行 DCE-MRI，使用 Tofts 药代动力学模型从数据中得出 K 和 v 的参数图像。
两种模型的肿瘤在贝伐单抗治疗后，微血管密度降低，血管周细胞覆盖率增加，血管成熟度增加。在 BK-12 模型中，与未经处理的肿瘤相比，贝伐单抗治疗的肿瘤缺氧程度更高，K 值更低，而未经处理和贝伐单抗治疗的 HL-16 肿瘤的缺氧分数和 K 值相似。在两种肿瘤模型中，中位 K 值与缺氧分数之间存在显著相关性，未经处理和贝伐单抗处理的肿瘤数据都可以通过同一曲线拟合。
与未经处理的肿瘤相比，贝伐单抗治疗的肿瘤显示出较少的异常微血管，但由于治疗引起的血管修剪，贝伐单抗治疗后微血管的整体功能可能受损，导致肿瘤缺氧增加。DCE-MRI 具有监测宫颈癌中贝伐单抗诱导的肿瘤缺氧变化的巨大潜力。
