How and when do tumor cells metastasize?

Tumor cells metastasize when they have successfully passed a number of invasion steps. We hypothesize that each step is a microecosystem, the basic elements of which are neoplastic cells, host cells, and extracellular matrix (ECM). We review here molecular pathways with a regulatory function in these microecosystems: homotypic cell-cell adhesion molecules counteracting invasion; complexes of lytic (pro-)enzymes, their receptors and inhibitors regulating focalized breakdown of the ECM; matrix components, their cellular receptors and motility factors governing cell migration; heterotypic cell-cell adhesion molecules initiating extravasation, encompassing in the vasculature the sequence: cell arrest, ECM lysis, cell migration; factors allowing survival and growth at ectopic sites. We conclude that delicate molecular balances within microecosystems are responsible for the temporary and repeated invasion events leading to metastasis.