The role of matrix stiffness in cancer stromal cell fate and targeting therapeutic strategies

Abstract

The tumor microenvironment (TME) is a complex macromolecular network filled with a series of stromal cells. It plays an important role in tumorigenesis, development, immune escape, drug resistance, and other processes and has received increasing attention in recent years. Currently, tumor cell-centered treatments are insufficient to eradicate malignancies, and researchers are constantly searching for better treatments. Over the past decade, the TME has been recognized as a rich resource for anti-cancer drug development. As a significant mechanical feature in the microenvironment of solid tumors, matrix stiffness is increased owing to stromal deposition and remodeling. The effect of matrix stiffness on cancer cells has been described in many studies, whereas its effect on cancer stromal cell fate has rarely been summarized. Therefore, this review discusses the relevant content and drug treatment studies targeting matrix stiffness. STATEMENT OF SIGNIFICANCE: Biochemical and biophysical interactions between tumor cells, stromal cells, and the extracellular matrix (ECM) co-create a distinct tumor microenvironment (TME), which impacts disease outcome. In recent years, there has been a greater emphasis on the physical properties of the ECM, with matrix stiffness being one of the most thoroughly investigated. The matrix stiffness of solid tumors is now commonly acknowledged to be greater than that of normal tissues. Cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), and endothelial cells (ECs) can all respond to matrix stiffness. At the same time, our current understanding of the TME is insufficient, and an in-depth examination of interactions between ECM and cells could lead to the development of more efficient and specialized treatments.

Keywords: Cancer-associated fibroblasts; Matrix stiffness; Stromal cells; Targeting therapies; Tumor microenvironment.