Liver Cancer Vascularity Driven by Extracellular Matrix Stiffness

Abstract

Background Extracellular matrix stiffness represents a barrier to effective local and systemic drug delivery. Increasing stiffness disrupts newly formed vessel architecture and integrity, leading to tumor-like vasculature. The resulting vascular phenotypes are manifested through different cross-sectional imaging features. Contrast-enhanced studies can help elucidate the interplay between liver tumor stiffness and different vascular phenotypes. Purpose This study aims to correlate extracellular matrix stiffness, dynamic contrast-enhanced computed tomography, and dynamic contrast-enhancement ultrasound imaging features of 2 rat hepatocellular carcinoma tumor models. Methods and Materials Buffalo-McA-RH7777 and Sprague Dawley (SD)–N1S1 tumor models were used to evaluate tumor stiffness by 2-dimensional shear wave elastography, along with tumor perfusion by dynamic contrast-enhanced ultrasonography and contrast-enhanced computed tomography. Atomic force microscopy was used to calculate tumor stiffness at a submicron scale. Computer-aided image analyses were performed to evaluate tumor necrosis, as well as the percentage, distribution, and thickness of CD34+ blood vessels. Results Distinct tissue signatures between models were observed according to the distribution of the stiffness values by 2-dimensional shear wave elastography and atomic force microscopy (P < 0.05). Higher stiffness values were attributed to SD-N1S1 tumors, also associated with a scant microvascular network (P ≤ 0.001). Opposite results were observed in the Buffalo-McA-RH7777 model, exhibiting lower stiffness values and richer tumor vasculature with predominantly peripheral distribution (P = 0.03). Consistent with these findings, tumor enhancement was significantly greater in the Buffalo-McA-RH7777 tumor model than in the SD-N1S1 on both dynamic contrast-enhanced ultrasonography and contrast-enhanced computed tomography (P < 0.005). A statistically significant positive correlation was observed between tumor perfusion on dynamic contrast-enhanced ultrasonography and contrast-enhanced computed tomography in terms of the total area under the curve and % microvessel tumor coverage (P < 0.05). Conclusions The stiffness signatures translated into different tumor vascular phenotypes. Two-dimensional shear wave elastography and dynamic contrast-enhanced ultrasonography adequately depicted different stromal patterns, which resulted in unique imaging perfusion parameters with significantly greater contrast enhancement observed in softer tumors.