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. 2019 Aug;22(3):457-470.
doi: 10.1007/s10456-019-09670-4. Epub 2019 May 30.

Monitoring tumour microenvironment changes during anti-angiogenesis therapy using functional MRI

Jianye Liang #  1 , Qingqing Cheng #  1 , Jiaxi Huang  1 , Mengjie Ma  1 , Dong Zhang  1 , Xueping Lei  2 , Zeyu Xiao  1 , Dongmei Zhang  3 , Changzheng Shi  4 , Liangping Luo  5
Affiliations

Monitoring tumour microenvironment changes during anti-angiogenesis therapy using functional MRI

Jianye Liang et al. Angiogenesis. 2019 Aug.

Abstract

Objective: This study aims to explore the feasibility of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and blood oxygen level-dependent magnetic resonance imaging (BOLD-MRI) in assessing vessel function and tumour aggressiveness during anti-angiogenesis treatment.

Materials and methods: A colon cancer xenograft model was established in BALB/C nude mice with the HCT116 cell line. Sixteen mice were randomly divided into Group A and Group B, which were treated with saline or bevacizumab by intraperitoneal injection on the 1st, 4th, 7th, 10th and 13th days and underwent DCE-MRI and BOLD-MRI examinations before and on the 3rd, 6th, 9th, 12th and 15th days after treatment. Group C was treated with oxaliplatin monotherapy, and Group D was treated with bevacizumab and oxaliplatin as a point of comparison for therapeutic effects. The pathological examinations included HE, HIF-1α, fibronectin and TUNEL staining, as well as α-SMA and CD31 double staining. One-way analysis of variance and correlation analysis were the main methods used for statistical analysis.

Results: Group D manifested the highest tumour inhibition rate and smallest tumour volume on day 15, followed by Group C, Group B and Group A. Ktrans (F = 81.386, P < 0.001), Kep (F = 45.901, P < 0.001), Ve (F = 384.290, P < 0.001) and R2* values (F = 89.323, P < 0.001) showed meaningful trends with time in Group B but not Group A. The Ktrans values and tumour vessel maturity index (VMI) were higher than baseline values 3-12 days after bevacizumab treatment. The CD31 positive staining rate and VMI had the strongest correlations with Ktrans values, followed by AUC180, Ve and Kep values. The R2* value positively correlated with the positive staining rates of HIF-1α and fibronectin.

Conclusion: Intermittent application of low-dose anti-angiogenic inhibitor treatment may help improve the effect of chemotherapy by reducing hypoxia-related treatment resistance and improving drug delivery. DCE-MRI is useful for evaluating vessel maturity and vascular normalization, while BOLD-MRI may help to predict tumour hypoxia and metastatic potential after anti-vascular treatment.

Keywords: Anti-angiogenesis treatment; BOLD-MRI; DCE-MRI; Hypoxia; Vascular normalization.

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