Tumor cells get primitive

Tumor cells get primitive hen 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 multi-cellular 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 W Venus dye trap catches executioners luorescence resonance energy transfer (FRET) between coupled fluorescent proteins is a promising tool for studying caspase activation during apoptosis. Unfortunately, current FRET systems are acutely sensitive to changes in pH and chloride ion concentration, and since these fluctuate considerably during apoptosis the results of FRET experiments are often difficult to interpret. Takemoto et al., whose report appears on page 235, developed a new FRET system that is resistant to acidification and chloride, and used it to obtain a detailed view of caspase-3 and caspase-9 activation in apoptosis. The new technique should also enable studies of caspase activity in vivo that were previously impossible. F Caspase 3 is activated first in the cytoplasm (left) and then in the nucleus (right). 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 lympho-cytes have been shown …