Mechanisms of Tumor Cell Invasion: Insights From the Perspective of Epithelial‐to‐Mesenchymal Transition

Tumor invasion implies aberrantly increased cell motility, and is the first step of the cascade of events culminating in the development of distant metastases. The emergence of migratory capacity in epithelial carcinomas, consisting essentially of stationary cells, is linked to the activation of the epithelial-to-mesenchymal transition (EMT) program that can range from partial to complete. According to the EMT model, carcinoma cells would weaken cell-cell junctions and extend basal pseudopodia into the interstitium to form adhesive contacts with the extracellular matrix there; eventually, the cytoskeleton would contract, causing the cell to move into the subjacent interstitium and, hence, initiate the actual invasion of the stroma. The so-called mesenchymal migration implies the appearance of protrusions at the cell front and contractile activity in the cell body and rear, effectively pulling the cell forward. The small GTPases of the Rho family play a crucial role in EMT and cell migration/invasion. The activity of Rac results in the development of a peripheral actin network that exerts a pushing force against the cell membrane at the cell front, leading to the formation of cytoplasmic extensions that establish adhesions with the matrix. Eventually, forward movement of the cell body is produced by Rho-mediated actomyosin contractility that generates traction force on the substrate. A second single cell migration strategy is called ameboid, and relies on strong contractility of the cytoskeleton generating high cytoplasmic pressure and, therefore, forward propulsion of the cell. A third mode of invasion is collective migration, whereby translocation of tumor cell clusters occurs thanks to partial EMT-converted leader cells at the front that guide the group of follower cells behind. Indeed, while single cell-based mesenchymal and ameboid invasion depend on complete EMT, collective invasion relies on partial EMT. However, depending on microenvironmental contexts, tumor cells can plastically switch from one of these modes to another.