Bi-Directional Signaling: Extracellular Matrix and Integrin Regulation of Breast Tumor Progression

Cell transformation and tumor progression involve a common set of acquired capabilities, including increased proliferation, failure of cell death, self-sufficiency in growth, angiogenesis, and tumor cell invasion and metastasis. The stromal environment consists of many cell types and various extracellular matrix (ECM) proteins that support normal tissue maintenance and which have been implicated in tumor progression. Both the chemical and mechanical properties of the ECM have been shown to influence normal and malignant cell behavior. For instance, mesenchymal stem cells differentiate into specific lineages that are dependent on matrix stiffness, while tumor cells undergo changes in cell behavior and gene expression in response to matrix stiffness. ECM remodeling is implicated in tumor progression and can result in increased deposition of stromal ECM, enhanced contraction of ECM fibrils, and altered collagen alignment and ECM stiffness. Tumor cells respond to changes in ECM remodeling through altered intracellular signaling and cell cycle control that lead to enhanced proliferation, loss of normal tissue architecture, and local tumor cell migration and invasion. This review focuses on the bi-directional interplay between the mechanical properties of the ECM and integrin-mediated signal transduction events in an effort to elucidate cell behaviors during tumor progression.