Order and Disorder: The Role of Extracellular Matrix in Epithelial Cancer

The central problem in cancer biology is to understand why tumor cells continue to survive and proliferate in situations where normal cells would arrest growth or apoptose. Although previous approaches have characterized cancer cells as autonomous entities and focused on the genetic mutations that contribute to tumor function, it is becoming increasingly clear that such models ignore the many ways in which cells interact with, and are regulated by, their surroundings. A different approach is to view cancer as a breakdown of the structural principles by which cells are organized within a tissue. In this review, we will provide some theoretical background for this approach, and describe some of our investigations in which we have found that either alterations in the microenvironment or altered perception of the microenvironment can cause normal cells to adopt tumorigenic behaviors. We will present an overview of the critical components of the cellular microenvironment, focusing on the large macromolecules that comprise the extracellular matrix (ECM). Then, we will summarize the large variety of cell surface adhesion molecules that sense and respond to the ECM and to neighboring cells. Finally, we will describe some of our recent investigations, in which we have used transgenic mice and a three dimensional (3D) cell culture assay to model the cell–ECM and cell–cell interactions that function to create mammary epithelial tissue. These experiments have helped define some of the molecular mechanisms by which mammary cells sense and respond to their microenvironment, how perturbations of those mechanisms can lead to breast tumors, and how reversal of those perturbations may be an approach to reverting early stage cancers.