Series Introduction: Invasive growth: from development to metastasis

Abstract

Invasive growthInvasive growth is a complex morphogenetic program in which proliferative responses are integrated by apparently independent events such as migration, survival, matrix degradation, and induction of cell polarity.In the first step of this sequence (Figure 1), a cell within a colony or solid tissue is instructed to disrupt cadherin-based intercellular junctions and acquire a fibroblastoid, motile phenotype, initiating detachment from the primary site of accretion.This dramatic reshaping is accompanied by cytoskeletal rearrangements and enhanced production of matrix proteases, which digest basal lamina components and facilitate cell movement through the surrounding environment.During this phase, invading cells must induce a constant and dynamic remodeling of integrin-mediated adhesive contacts with the ECM, which provides a mechanical support for cell migration and prevents the induction of apoptosis.Cell depolarization and invasion are followed by stimulation of cell growth, which allows new regions of the extracellular environment to become populated with cells, setting the stage for the restoration of normal tissue complexity.Ultimately, these cells stop dividing, repolarize, and start terminal differentiation, arranging themselves into three-dimensional structures that are usually organized as branching tubules (1). Invasive growth in normal developmentNot surprisingly, the physiological conditions for invasive growth are found in embryonic and fetal development.For instance, during epithelial morphogenesis, cells form ramified tubules and papillary outgrowths that compose the parenchymal architecture of several organs, including exocrine glands, gut, liver, and kidney.Similarly, the clustering and reorganization of angioblasts to form capillary-like structures during vasculogenesis, and the formation of new capillaries by sprouting or splitting from pre-existing vessels during angiogenesis, represent two other examples of invasive growth.A specialized aspect of this phenomenon is observed in the wiring of the nervous system, when axons must elongate and emit ramifications to attain targets that are often significant distances away.Although best documented in cells of epithelial, endothelial, and neural origin, invasive growth also takes place in other tissues.In the bone marrow, it occurs when hemopoietic precursors dissociate from their niches, migrate, cross blood vessel walls, and even-