MRI measurements of vessel calibre in tumour xenografts: Comparison with vascular corrosion casting

Jake S Burrell,Robert S Bradley,Simon Walker-Samuel,Yann Jamin,Lauren C.J Baker,Jessica K.R Boult,Philip J Withers,Jane Halliday,John C Waterton,Simon P Robinson

doi:10.1016/j.mvr.2012.08.001

Abstract

Vessel size index (Rv, μm) has been proposed as a quantitative magnetic resonance imaging (MRI) derived imaging biomarker in oncology, for the non-invasive assessment of tumour blood vessel architecture and vascular targeted therapies. Appropriate pre-clinical evaluation of Rv in animal tumour models will improve the interpretation and guide the introduction of the biomarker into clinical studies. The objective of this study was to compare Rv measured in vivo with vessel size measurements from high-resolution X-ray computed tomography (μCT) of vascular corrosion casts measured post mortem from the same tumours, with and without vascular targeted therapy. MRI measurements were first acquired from subcutaneous SW1222 colorectal xenografts in mice following treatment with 0 (n=6), 30 (n=6) or 200mg/kg (n=3) of the vascular disrupting agent ZD6126. The mice were then immediately infused with a low viscosity resin and, following polymerisation and maceration of surrounding tissues, the resulting tumour vascular casts were dissected and subsequently imaged using an optimised μCT imaging approach. Vessel diameters were not measurable by μCT in the 200mg/kg group as the high dose of ZD6126 precluded delivery of the resin to the tumour vascular bed. The mean Rv for the three treatment groups was 24, 23 and 23.5μm respectively; the corresponding μCT measurements from corrosion casts from the 0 and 30mg/kg cohorts were 25 and 28μm. The strong association between the in vivo MRI and post mortem μCT values supports the use of Rv as an imaging biomarker in clinical trials of investigational vascular targeted therapies.

Highlights

Susceptibility contrast magnetic resonance imaging (MRI) can be used for the non-invasive determination of vessel size (Rv, μm) and fractional blood volume (Tropres et al, 2001)
The number of significantly enhancing voxels in the MRI image maps was seen to decrease between vehicle and treated groups, and this effect was more exaggerated in tumours from mice treated with 200 mg/kg than 30 mg/kg ZD6126
Quantitation of the MRI data revealed that, compared to the vehicle group, fBV was lower in tumours treated with either 30 or 200 mg/kg ZD6126, and was highly significant (p b 0.01) in the cohort treated with 200 mg/kg (Table 1)

Summary

Introduction

Susceptibility contrast magnetic resonance imaging (MRI) can be used for the non-invasive determination of vessel size (Rv, μm) and fractional blood volume (fBV, %) (Tropres et al, 2001). These quantitative imaging biomarkers have been exploited in vivo to evaluate incipient tumour vascular architecture and function (Douma et al, 2010; Farrar et al, 2010; Kostourou et al, 2003; Lemasson et al, in press; Remmele et al, 2011; Robinson et al, 2003b, 2008; Wade and Kozlowski, 2007), and tumour response to anti-vascular therapies (Beaumont et al, 2009; Howe et al, 2008; Lemasson et al, 2011; Nielsen, 2007; Ungersma et al, 2010; Valable et al, 2008; Walker-Samuel et al, 2012). The remaining detailed replication of the vascular network allows for a submicrometer resolution of the cast surface when analysed in the scanning electron microscope, revealing the nature of the blood vessel under investigation

Objectives

Methods

Results

Conclusion