Purpose: The tumor microenvironment presents with altered extracellular matrix (ECM) and stroma composition which may affect treatment efficacy and contribute to tissue stiffness. Ultrasound (US) elastography can visualize and quantify tissue stiffness non-invasively. However, the contributions of ECM and stroma components to stiffness are poorly understood. We therefore set out to quantify ECM and stroma density and their relation to tumor stiffness. Experimental Design: A modified clinical ultrasound system was used to measure tumor stiffness and perfusion during tumor growth in pre-clinical tumor models. In vivo measurements were compared with collagen mass spectroscopy and automatic analysis of matrix and stroma markers derived from immunofluorescence images. Results: US elastography estimates of tumor stiffness were positively correlated with tumor volume in collagen and myofibroblast-rich tumors, while no correlations were found for tumors with low collagen and myofibroblast content. US elastography measurements were strongly correlated with ex vivo mechanical testing and mass spectroscopy-based measurements of total collagen and immature collagen crosslinks. Registration of ultrasound and confocal microscopy data showed strong correlations between blood vessel density and T-cell density in syngeneic tumors, while no correlations were found for genetic tumor models. In contrast to collagen density, which was positively correlated with stiffness, no significant correlations were observed for hyaluronic acid density. Finally, localized delivery of collagenase led to a significant reduction in tumor stiffness without changes in perfusion 24 hours after treatment. Conclusions: US elastography can be used as a potential biomarker to assess changes in the tumor microenvironment, particularly changes affecting the ECM.
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