Impact of stroma remodeling on forces experienced by cancer cells and stromal cells within pancreatic tumor tissue

Abstract

Abstract Remodeling (re-engineering) of a tumor’s stroma can improve the efficacy of antitumor therapies, without destroying the stroma. However, it still remains elusive how the remodeling of stromal components is associated with the penetration of nanoparticles. A major lack of knowledge is felt for discerning which stromal components hinder the reach of nanoparticles deep into cancer cells. In this study, our first objective is to determine how stromal remodeling alters the stress experienced by cancer cells and the stromal cells within pancreatic tumor tissue. Physical stresses exerted on cancer cells by their microenvironment have been shown to drive cells toward invasive phenotype by altering cells’ motility, proliferation, and apoptosis. Our second objective is to identify the remodeling of which stromal component has highest impact on stresses experienced by cancer cells. Our assumption is that the medication applied for stromal remodeling change stiffness of fibroblasts and extracellular matrix (ECM). We have developed a three-dimensional model of tumor tissue consisting of cancer cells, stromal cells, and ECM. We have applied this model to investigate the impact of different remodeling degrees on cancer cells and stromal cells by quantifying stresses experienced by these components. Our results how that remodeling induced softening of ECM will significantly increase the magnitude of stresses within tumor tissue. Furthermore, our results reveal that the remodeling induced softening of ECM has higher impact on smaller tumors while softening of stromal cells show its significant influence on larger tumors. Our study provides unique knowledge on the characteristic factors for remodeling of tumor microenvironment’s components with an ultimate goal of leveraging this knowledge to overcome a tumor’s resistance against the penetration of nanoparticles on a per-patient basis. Without the distinct identification of the tumor microenvironment’ role in the resistance of tumor stroma to nanoparticles’ penetration, all attempts to improve drug therapies’ success will remain out of reach.