Assessment of the hepatic tumor extracellular matrix using elastin-specific molecular magnetic resonance imaging in an experimental rabbit cancer model

Sarah Keller,Daniel Schulze,Julia Brangsch,Uwe Karst,Marcus R Makowski,Rebecca Buchholz,Avan Kader,Jan O Kaufmann,Bernd Hamm,Eyk Schellenberger,Tabea Borde,Carolin Reimann

doi:10.1038/s41598-020-77624-8

Abstract

To investigate the imaging performance of an elastin-specific molecular magnetic resonance imaging (MRI) probe with respect to the extracellular matrix (ECM) in an experimental hepatic cancer model. Twelve rabbits with hepatic VX2 tumors were examined using 3 T MRI 14, 21, and 28 days after tumor implantation for two subsequent days (gadobutrol, day 1; elastin-specific probe, day 2). The relative enhancement (RE) of segmented tumor regions (central and margin) and the peritumoral matrix was calculated using pre-contrast and delayed-phase T1w sequences. MRI measurements were correlated to histopathology and element-specific and spatially resolved mass spectrometry (MS). Mixed-model analysis was performed to assess the performance of the elastin-specific probe. In comparison to gadobutrol, the elastin probe showed significantly stronger RE, which was pronounced in the tumor margin (day 14–28: P ≤ 0.007). In addition, the elastin probe was superior in discriminating between tumor regions (χ2(4) = 65.87; P < 0.001). MRI-based measurements of the elastin probe significantly correlated with the ex vivo elastinstain (R = .84; P <0 .001) and absolute gadolinium concentrations (ICP-MS: R = .73, P <0 .01). LA-ICP-MS imaging confirmed the colocalization of the elastin-specific probe with elastic fibers. Elastin-specific molecular MRI is superior to non-specific gadolinium-based contrast agents in imaging the ECM of hepatic tumors and the peritumoral tissue.

Highlights

To investigate the imaging performance of an elastin-specific molecular magnetic resonance imaging (MRI) probe with respect to the extracellular matrix (ECM) in an experimental hepatic cancer model
Assuming that hepatic tumors have an increased expression of collagens, including e lastin[10], the hypothesis arises that elastin-specific contrast agents allow for a more clearly defined enhancement and differentiation of tumor regions based on the composition of their ECM than conventional gadolinium-based contrast agents
After intravenous contrast agent administration of gadobutrol on day 1, there was a shallow enhancement of the tumor regions, accentuated during the venous and late contrast agent phase

Summary

Introduction

To investigate the imaging performance of an elastin-specific molecular magnetic resonance imaging (MRI) probe with respect to the extracellular matrix (ECM) in an experimental hepatic cancer model. Elastin-specific molecular MRI is superior to non-specific gadolinium-based contrast agents in imaging the ECM of hepatic tumors and the peritumoral tissue. Molecular elastin-specific MR contrast agents have been already successfully used to study the ECM remodeling in cardiovascular disease with results indicating a large translational p otential[22,23,24] In this context, elastinspecific molecular MRI could quantify the elastin content in arteriosclerotic plaques on the basis of signal intensity, and predict potential rupture sites in the course of an aortic aneurysm in follow-up studies[22,23]. Assuming that hepatic tumors have an increased expression of collagens, including e lastin[10], the hypothesis arises that elastin-specific contrast agents allow for a more clearly defined enhancement and differentiation of tumor regions based on the composition of their ECM than conventional gadolinium-based contrast agents

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