Preclinical Three-Dimensional Vibrational Shear Wave Elastography for Mapping of Tumour Biomechanical Properties In Vivo

SIMPLE SUMMARY: The increased tissue stiffness associated with cancer has been found to be a significant barrier to effective treatment and indicates an increased likelihood of cancer progression. Techniques to map tumour stiffness throughout the whole tumour in three dimensions will assist with preclinical research that aims to understand the relationship between the stiffness, the underlying tumour biology, and the response of tumours to therapy. We have developed an approach that measures the tumour stiffness in murine models of cancer, which are commonly used for cancer research. This technique uses a high-frequency vibrational source, ultrasound imaging and a three-dimensional analysis, which has advantages in terms of spatial resolution and rapid acquisition times. Here we present the first successful demonstration of the non-invasive three-dimensional measurement of tumour stiffness in two preclinical tumour models and the ability of the technique to detect a change in tumour stiffness in response to an anti-cancer drug. ABSTRACT: Preclinical investigation of the biomechanical properties of tissues and their treatment-induced changes are essential to support drug-discovery, clinical translation of biomarkers of treatment response, and studies of mechanobiology. Here we describe the first use of preclinical 3D elastography to map the shear wave speed (c(s)), which is related to tissue stiffness, in vivo and demonstrate the ability of our novel 3D vibrational shear wave elastography (3D-VSWE) system to detect tumour response to a therapeutic challenge. We investigate the use of one or two vibrational sources at vibrational frequencies of 700, 1000 and 1200 Hz. The within-subject coefficients of variation of our system were found to be excellent for 700 and 1000 Hz and 5.4 and 6.2%, respectively. The relative change in c(s) measured with our 3D-VSWE upon treatment with an anti-vascular therapy ZD6126 in two tumour xenografts reflected changes in tumour necrosis. U-87 MG drug vs vehicle: Δc(s) = −24.7 ± 2.5 % vs 7.5 ± 7.1%, (p = 0.002) and MDA-MB-231 drug vs vehicle: Δc(s) = −12.3 ± 2.7 % vs 4.5 ± 4.7%, (p = 0.02). Our system enables rapid (<5 min were required for a scan length of 15 mm and three vibrational frequencies) 3D mapping of quantitative tumour viscoelastic properties in vivo, allowing exploration of regional heterogeneity within tumours and speedy recovery of animals from anaesthesia so that longitudinal studies (e.g., during tumour growth or following treatment) may be conducted frequently.