Protease-inhibited cells squeeze through the matrix using ameboid-like movements.

When metastatic tumor cells migrate through connective tissue, they use proteases to chew a path for themselves. This finding led to the development of protease inhibitors as potential cancer therapies, but some animal and human clinical tests of these drugs have been disappointing. Wolf et al., reporting on page 267, may have found one reason why: when proteolysis is inhibited, tumor cells resort to an amoeboid type of movement that allows them to squeeze through cracks in the matrix. The results provide substantial new insight into cell migration in multicellular organisms.

Using both in vitro and in vivo cell migration systems, the authors investigated the effects of inhibiting proteases that degrade the extracellular matrix. Normally, transformed cells migrate through three-dimensional collagen matrices or the mouse dermis as individual, spindle-shaped cells, using several proteolytic enzymes and leaving trails through the matrix. When the proteases are shut down, cells undergo a striking change in their appearance, reminiscent of a transition toward amoeboid movement. The cells then continue to migrate through the matrix without breaking it down and without leaving trails.

The change in migration strategy, which Wolf et al. call the mesenchymal–amoeboid transition, suggests that the cells of multicellular organisms retain a more primitive migration system that is normally masked. This type of migration, similar to the movement of the soil amoeba Dictyostelium discoideum, could serve as a “salvage” pathway, allowing tumor cells to take a step backward in evolutionary time to continue migrating in the presence of protease inhibitors.

Amoeboid movement may also have more positive functions in multicellular organisms; in separate work, T lymphocytes have been shown to migrate through collagen matrices without using proteases. The authors are now trying to identify the regulatory pathways responsible for controlling the mesenchymal–amoeboid transition. Targeting this process while simultaneously inhibiting proteases might provide a salvage pathway for new tumor therapies as well. ▪