Collective invasion of cancer: Perspectives from pathology and development

Clinical pathologists have long been aware that in many types of human malignant tumors, the cells are often connected and form groups of various sizes or "nests". In this way, they achieve "collective invasion" into the surrounding stroma, rather than spreading out individually. Such collective behavior is also a common feature of migration during embryonic and postnatal developmental stages, suggesting there are advantages gained by collective cell migration in the organisms. Recent studies have revealed the mechanisms underlying the collective invasion of cancer cells. These mechanisms differ from those observed in the migration of single cells in culture, including reliance on the epithelial-mesenchymal transition program. Whereas intercellular adhesion appears to be coordinated, cancer cell groups can be heterogenous, including cells that are leaders and those that are followers. There is also interaction with the tumor microenvironment that is a prerequisite for collective invasion of cancer. In this review, we describe recently emerging mechanisms underlying the collective migration of cells, with a particular focus in our studies on the actin-binding protein Girdin/GIV and the transcriptional regulator tripartite motif containing 27. These studies provide new perspectives on the mechanistic analogy between cancer and development.