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Enhanced chemokinetic and chemotactic motility stimulated by signals transduced through the ErbB family of receptors has been shown to play a critical role in tissue invasion by a variety of solid tumor types. Most efforts in studying the role of the epidermal growth factor receptor (EGFR) and its downstream signals in regulating the biophysical processes of cell motility have been carried out in two-dimensional (2D) systems, whereas in vivo migration occurs through three-dimensional (3D) spaces consisting of the extracellular matrix (ECM). With the additional mechanical and sterical influences posed by the ECM, disruption of EGFR-signaling components of cells migrating in 3D may exhibit effects that are distinct from 2D cell migration.

In this work, we developed and optimized a 3D time-lapse confocal microscopy technique to image and quantify real-time 3D migration behavior of individual U87MG human glioblastoma cells sparsely seeded in collagen I gels. EGF stimulation exhibited matrix-concentration dependent increase in 3D cell scattering through both greater cell speed and greater directional persistence. This was in contrast to previous reports that EGF stimulation leads to an increased cell speed, but a decrease in persistence in 2D. Over-expression of Mena, a target downstream of EGFR, in U87MG cells led to decrease in persistence on 2D surfaces, but was correlated with increased persistence in 3D and in vivo. Supported by computer simulations, we propose that low directional persistence in 2D may, at least under some conditions, translate into high directional persistence in a porous 3D ECM network.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA