Objective: To evaluate the feasibility of intravoxel incoherent motion diffusion-weighted magnetic resonance imaging (IVIM-DWI MRI) in the evaluation of tumor vascular normalization in a mouse model of colorectal cancer induced by recombinant human endostatin (rhES). Methods: The CT26 colorectal cancer xenograft model of BALB/c mice were established and divided into rhES group and control group, with 20 mice in each group. The mice of rhES group were intravenously injected with rhES 5 mg·kg(-1)·d(-1) once daily for 12 days, while the mice of the control group were intravenously injected with the same volume of 0.9% saline. 5 mice of rhES group and control group were randomly selected to perform IVIM-DWI MRI as following times: before treatment and four, eight, twelve days after treatment. The parameters of IVIM-DWI were recorded, including true diffusion coefficient(D), pseudo-diffusion coefficient (D(*)) and perfusion fraction (f). Meanwhile, microvessel density (MVD), pericyte coverage and tumor perfusion in tumor tissues were detected by immunofluorescence, respectively. Results: The tumor volumes of control group and rhES group before treatment were (154.42±24.65) mm(3) and (174.24±28.27)mm(3,) respectively, without statistically significant difference (P=0.440). From day 2 to day 12 after treatment, the tumor volume of rhES group was significantly smaller than that of control group (all P<0.05). There were no statistical significances of D value between the rhES group and control group before and after treatment (all P>0.05). The D(*) values of the rhES group were (10.940±2.834)×10(-3)mm(2)/s and (12.940±2.801)×10(-3)mm(2)/s in day 4 and 8 after treatment respectively, significantly higher than (6.980±1.554)×10(-3)mm(2)/s and (7.898±1.603)×10(-3)mm(2)/s of control group (P<0.05). Moreover, compared with control group, the D(*) value of rhES group was significantly lower in day 12 (6.848±1.460)×10(-3)mm(2)/s vs (9.950±2.596)×10(-3)mm(2)/s, (P<0.05). The f value of rhES group in day 8 was (0.226±0.021)%, significantly higher than (0.178±0.016)% of control group (P<0.01). The MVD of rhES group was significantly lower than that of control group (P<0.05), while the pericyte coverage and tumor perfusion of rhES group were significantly higher than those of control group in day 4 and 8 after treatment (all P<0.05). In addition, we found D(*) value of IVIM-DWI in rhES group was significantly related with MVD, pericyte coverage and tumor perfusion (r=-0.354, r=0.555, r=0.559, all P<0.05). Meanwhile, the f value in rhES group was also significantly related with MVD, pericyte coverage and tumor perfusion (r=-0.391, r=0.538, r=0.315, all P<0.05). Conclusions: IVIM-DWI MRI can effectively evaluate the vascular normalization in rhES-induced CT26 colorectal tumor.The parameters D(*) and f are closely related to intratumorally microvessel density, pericyte coverage and perfusion, which can effectively monitor the occurrence of tumor vascular normalization time.
目的： 探讨体素内不相干运动扩散加权磁共振成像(IVIM－DWI MRI)评价重组人血管内皮抑素(rhES)诱导的结直肠癌小鼠模型肿瘤血管正常化的可行性。 方法： 建立BALB/c小鼠CT26结直肠癌移植瘤模型，分为rhES组和对照组，每组20只。rhES组静脉注射rhES 5 mg·kg(－1)·d(－1)，1次/d，连用12 d；对照组静脉注射同体积生理盐水。rhES组和对照组分别在干预前和干预后第4天、第8天和第12天随机选取5只小鼠进行磁共振扫描，得到IVIM－DWI相关参数[真弥散系数(D)、伪弥散系数(D(*))和灌注分数(f)]，以免疫荧光法检测微血管密度(MVD)、周细胞覆盖率和肿瘤内灌注情况。 结果： 干预前，对照组小鼠的肿瘤体积为(154.42±24.65)mm(3)，rhES组小鼠的肿瘤体积为(174.24±28.27)mm(3)，差异无统计学意义(P＝0.440)。干预后第2天至第12天，对照组和rhES组小鼠的肿瘤体积均呈持续性增长趋势，但rhES组小鼠的肿瘤体积始终明显低于对照组(均P<0.05)。rhES组和对照组的D值在各时间点的差异均无统计学意义(均P>0.05)。rhES组干预后第4天和第8天的D(*)值分别为(10.940±2.834)×10(－3) mm(2)/s和(12.940±2.801)×10(－3) mm(2)/s，较对照组[分别为(6.980±1.554)×10(－3) mm(2)/s和(7.898±1.603)×10(－3) mm(2)/s]明显增高(均P<0.05)。但rhES组干预后第12天的D(*)值为(6.848±1.460)×10(－3) mm(2)/s，较对照组[(9.950±2.596)×10(－3) mm(2)/s]明显降低(P<0.05)。rhES组干预后第8天的f值为(0.226±0.021)%，明显高于对照组[(0.178±0.016)%，P<0.01]。干预后第4天和第8天，rhES组小鼠瘤体微血管密度(MVD)较对照组明显降低(P<0.05)，而周细胞覆盖率和肿瘤内灌注率较对照组明显升高(均P<0.05)。rhES组D(*)值与MVD、周细胞覆盖率和肿瘤内灌注率均明显相关(r值分别为－0.354、0.555和0.559，均P<0.05)，f值与MVD、周细胞覆盖率和肿瘤内灌注率亦明显相关(r值分别为－0.391、0.538和0.315，均P<0.05)。 结论： IVIM－DWI MRI可有效评估rhES诱导的CT26结直肠癌血管正常化，其参数D(*)、f与肿瘤内MVD、周细胞覆盖率和肿瘤内灌注率密切相关，能有效监测肿瘤血管正常化时间窗的发生。.
Keywords: Angiogenesis; Colorectal neoplasms; Diffusion magnetic resonance imaging; Intravoxel incoherent motion; Recombinant human endostatin; Vascular normalization.