Monitoring The Tumor Vascular Normalization In Colorectal Cancer Mouse Induced By Recombinant Human Endostatin With Intravoxel Incoherent Motion Diffusion-Weighted Magnetic Resonance Imaging

Objective:To evaluate the feasibility of intravoxel incoherent motion diffusion-weighted magnetic resonance imaging(IVIM-DWI MRI)in monitoring 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 was established and divided into rhES group and control group,with 20 mice in each group.The mice of rhES group were intravenous injected rhES 5 mg/kg/d once daily for 12 days,while the mice of the control group were intravenous injected the same volume of 0.9%saline.5 mice of rheas’ 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 volume of control group and rue’s group before treatment were(154.42±24.65)mm3 and(174.24±28.27)mm3,respectively,without statistically significant difference(P=0.440).From day 2 to day 12 after treatment,the tumor volume of two groups both kept growing,while the tumor volume of rhES group was significantly smaller than that of control group(all P<0.05).There was no statistical significance of D value between the rhES group and control group before and after treatment(all P>0.05).The D*value of the rhES group were(10.94±2.834)×10-3mm2/s and(12.940±2.801)×10-3mm2/s in day 4 and 8 after treatment respectively,which was significantly higher than(6.980±1.554)x10-3mm2/s and(7.898±1.603)×10-3mm2/s of control group(all P<0.05).Moreover,compared with control group,the D*value of rhES group was significantly lower in day 12 after treatment[(6.848±1.460)×10-3 mm2/s vs(9.950±2.596)×10-3mm2/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 the control group(all P<0.05),while the pericyte coverage and tumor perfusion of rhES group were significantly higher than control group in day 4 and 8 after treatment(all P<0.05).In addition,the study 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).Conclusion:The tumor vascular normalization in CT26 colorectal cancer mouse induced by rhES is from day 4 to day 8 after intervention.The parameters D*and f of IVIM-DWI MRI are closely related to intratumorally microvessel density,pericyte coverage and perfusion,which can effectively monitor the occurrence of rhES-induced CT26 colorectal tumor vascular normalization time.