Longitudinal in vivo MR elastography reveals whole-liver viscoelastic involvement in a murine model of hepatocellular carcinoma

Abstract

Cancer cells actively shape their microenvironment and adapt the physical and biomechanical properties of the host tissue. However, for organs like the liver, especially in vivo, it remains unclear at what rate and spatial extent macroscopic viscoelastic properties change during formation of a cancer-permissive environment. Using clinical multifrequency magnetic resonance elastography (MRE) in a mouse model of hepatocellular carcinoma (HCC), we identified surprisingly early and large-scale viscoelasticity changes leading to whole-liver biomechanical involvement stretching far beyond the local cancer microenvironment. Widespread liver softening began two weeks after HCC inoculation, followed by a decrease in tissue viscosity and fluidity two weeks later, preceding any macroscopic evidence of local tumor growth. In contrast, local lesions with stiff-rigid biomechanical properties were not detectable by standard MRI and MRE until five to six weeks post-injection. Furthermore, tumor viscoelasticity correlated with that of the host liver, also suggesting a possible widespread adaptation of the biomechanical properties beyond the tumor margins and its local niche during early liver colonization. The observed large-scale viscoelastic signature, detectable just two weeks after tumor cells injection, could serve as a non-invasive imaging biomarker to inform physicians about tumor niche formation and liver cancer progression long before any macroscopic manifestation of solid tumors.