gms | German Medical Science

Tumor cell migration through connective tissue requires adhesive cell matrix interactions provided by surface integrins and other adhesion molecules. We have investigated-, whether tumor cell migration in 3D ECM environments is fully abrogated by blocking integrin functions and whether compensation mechanisms might support migratory rescue. Within 3D collagen matrices, highly invasive MV3 melanoma cells preferentially utilize α2β1 integrins for elongation, adhesion to collagen fibers, fiber bundling, force generation, and migration. Using these cells, β1 integrin function was reduced by i) flow cytometric sorting for subsets expressing low integrin levels; ii) blocking anti β1 mAb 4B4 at different concentrations; iii) rhodocetin, a selective α2β1 integrin inhibitor. Each of these strategies lowering β1 integrin function resulted in a varying yet incomplete reduction of migration rates accompanied by the conversion from fibroblastlike spindle-shaped morphology to more spherical amoeboid morphodynamics, and concomitantly abolished capacity to contract and remodel 3D collagen lattices. Residual amoeboid migration efficiencies amounted to undiminished 0,3- 0,4 µm/min in faster and 0,03-0,1 µm/min in slower cell subsets, sustained by propulsion and squeezing along matrix gaps provided by a strictly cortical actin cytoskeleton, yet lacking integrin and actin focalization at cell-matrix interactions. These findings were extended using fibroblast-like cells derived from β1-/- ES cells (GD25) and β1-/- murine fibroblasts, which exhibited slow (GD25) or fast amoeboid movement (β1-/- fibroblasts) after β1 integrin deletion. After simultaneous inhibition of ß1, αvβ3, and GAG-mediated cell-ECM interactions the residual migration was significantly reduced to minimal residual movement below 0.02 µm/min and a completely nonmoving fraction of greater 60%. In conclusion, mesenchymal-amoeboid transition after abrogation of β1 integrin function is a rescue mechanism supporting residual tumor cell migration by low- or non- adhesive mechanisms through the surface glycocalyx.