Extracellular Matrix Remodeling and Stiffening Modulate Tumor Phenotype and Treatment Response

Abstract

Solid tumors are characterized by a remodeled and stiffened extracellular matrix. The extracellular matrix is not a passive by-product of the tumor, but actively compromises tissue-specific differentiation, enhances tumor cell proliferation and survival, and fosters tumor cell invasion and migration. The tumor extracellular matrix also influences the behavior of the stromal cells, which through vicious, feedforward-reinforcing pathways promote tumor progression and compromise treatment efficacy. To investigate how the tumor extracellular matrix alters cancer phenotype and treatment, a number of three-dimensional, organotypic culture models have been developed that employ a variety of materials, including natural matrices, collagen, fibrin, and reconstituted basement membrane gels, as well as synthetic hydrogel materials such as polyacrylamide and polyethylene glycol. These models have been used to interrogate how specific microenvironmental features modify tumor and stromal cell function and to identify the molecular mechanisms that regulate tumorigenesis and therapeutic efficacy. To translate these findings into more effective treatment strategies for patients, clinically informed studies are needed that incorporate computational modeling and in vivo validation.