Evaluation of growth-induced, mechanical stress in solid tumors and spatial association with extracellular matrix content

Abstract

Mechanical stresses in solid tumors play an important role in tumor progression and treatment efficacy but their quantification is under-investigated. Here, we developed an experimental and computational approach to calculate growth-induced, residual stresses and applied it to the breast (4T1), pancreatic (PAN02), and fibrosarcoma (MCA205) tumor models. Following resection, tumors are embedded in agarose gels and cuts are made in two perpendicular directions to release residual stress. With the use of image processing, the detailed bulging displacement profile is measured and finite elements models of the bulging geometry are developed for the quantification of the stress levels. The mechanical properties of the tumors are measured in vivo prior to resection with shear wave elastography. We find that the average magnitude of residual stresses ranges from 3.31 to 10.88 kPa, and they are non-uniformly distributed within the tissue due to the heterogeneity of the tumor microenvironment. Interestingly, we demonstrate that a second cut can still release a significant amount of stresses. We further find a strong association of spatial hyaluronan and collagen content with the spatial profile of stress for the MCA205 and PAN02 tumors and a partial association for the 4T1. Interestingly the colocalization of hyaluronan and collagen content had a stronger association with the spatial profile of stress for MCA205, PAN02, and 4T1. Finally, measurements of the elastic modulus with shear wave elastography show a nonlinear correlation with tumor volume for the more fibrotic MCA205 and 4T1 tumors. Overall, our results provide insights for a better understanding of the mechanical behavior of tumors.