Tumor cells exhibit at least two distinct modes of migration when invading the 3D environment. A single tumor cell’s invasive strategy follows either mesenchymal or amoeboid patterns. Certain cell types can use both modes of invasiveness and undergo transitions between them. This work outlines the signaling pathways involved in mesenchymal and amoeboid types of tumor cell motility and summarizes the molecular mechanisms that are involved in transitions between them. The focus is on the signaling of the Rho family of small GTPases that regulate the cytoskeleton-dependent processes taking place during the cell migration. The multiple interactions among the Rho family of proteins, their regulators and effectors are thought to be the key determinants of the particular type of invasiveness. Mesenchymal and amoeboid invasive strategies display different adhesive and proteolytical interactions with the surrounding matrix and the alterations influencing these interactions can also lead to the transitions.

In solid cancers, invasion and metastasis account for more than 90% of mortality. However, in the current armory of anticancer therapies, a specific category of anti-invasion and antimetastatic drugs is missing. Here, we coin the term ‘migrastatics’ for drugs interfering with all modes of cancer cell invasion and metastasis, to distinguish this class from conventional cytostatic drugs, which are mainly directed against cell proliferation. We define actin polymerization and contractility as target mechanisms for migrastatics, and review candidate migrastatic drugs. Critical assessment of these antimetastatic agents is warranted, because they may define new options for the treatment of solid cancers.

Intermediate filaments constitute the third component of the cellular skeleton. Unlike actin and microtubule cytoskeletons, the intermediate filaments are composed of a wide variety of structurally related proteins showing distinct expression patterns in tissues and cell types. Changes in the expression patterns of intermediate filaments are often associated with cancer progression; in particular with phenotypes leading to increased cellular migration and invasion. In this review we will describe the role of vimentin intermediate filaments in cancer cell migration, cell adhesion structures, and metastasis formation. The potential for targeting vimentin in cancer treatment and the development of drugs targeting vimentin will be reviewed.

Cancer is a deadly disease primarily because of the ability of tumor cells to spread from the primary tumor, to invade into the connective tissue, and to form metastases at distant sites. In contrast to cell migration on a planar surface where large cell tractions and contractile forces are not essential, tractions and forces are thought to be crucial for overcoming the resistance and steric hindrance of a dense 3-dimensional connective tissue matrix. In this review, we describe recently developed biophysical tools including 2-D and 3-D traction microscopy to measure contractile forces of cells. We discuss evidence indicating that tumor cell invasiveness is associated with increased contractile force generation.

During malignant neoplastic progression the cells undergo genetic and epigenetic cancer-specific alterations that finally lead to a loss of tissue homeostasis and restructuring of the microenvironment. The invasion of cancer cells through connective tissue is a crucial prerequisite for metastasis formation. Although cell invasion is foremost a mechanical process, cancer research has focused largely on gene regulation and signaling that underlie uncontrolled cell growth. More recently, the genes and signals involved in the invasion and transendothelial migration of cancer cells, such as the role of adhesion molecules and matrix degrading enzymes, have become the focus of research. In this review we discuss how the structural and biomechanical properties of extracellular matrix and surrounding cells such as endothelial cells influence cancer cell motility and invasion. We conclude that the microenvironment is a critical determinant of the migration strategy and the efficiency of cancer cell invasion.