Wounds that will not heal: pervasive cellular reprogramming in cancer

Abstract

There has been an explosion of articles on epithelial-mesenchymal transition and other modes of cellular reprogramming that influence the tumor microenvironment. Many controversies exist and remain to be resolved. The interest of the pathologists in the molecular and functional parallels between wound healing and the developing tumor stroma has its earliest origin in the writings of Rudolph Virchow in the 19(th) century. Since then, most of the focus has been primarily on the dynamics of the extracellular matrix; however, new interest has been redirected toward deciphering and understanding the enigmatic, yet elegant, plasticity of the cellular components of the proliferating epithelia and stroma and how they are reciprocally influenced. Citing several examples from breast cancer research, we will trace how these perspectives have unfolded in the pages of The American Journal of Pathology and other investigative journals during the past century, their impact, and where the field is headed.

Figure 1

Schematic diagram of the diverse cellular reprogramming that occurs during wound healing responses in the tumor stroma. Cellular processes are italicized. Indicated are reversible transitions between 1) epithelial cells and mesenchymal phenotypes, 2) M1 macrophages and M2 macrophages, 3) fibroblasts and myofibroblasts, 4) endothelial cells and myofibroblasts, and 5) pericytes and myofibroblasts. CCL, chemokine C-C motif ligand; FGF, fibroblast growth factor.