Posted by: Dan | July 19, 2006

Understanding Tumor Cell Migration in 3D Matrices

The current issue of PNAS has an interesting paper trying to delineate the differences in migration on 2D versus 3D settings: Migration of tumor cells in 3D matrices is governed by matrix stiffness along with the cell-matrix adhesion and proteolysis. Zaman et al. give this account of the previous descreptancies between in vitro and in vivo migration, with their proposed means of explaining the differences:

…the conceptual and computational models developed for migration on 2D surfaces do not account for the full complexity of migration through a 3D gel such as the roles of biochemical factors (e.g., the distribution of cell/matrix attachments over the entire cell), steric factors such as hindrance by fibers of the matrix, and mechanical factors such as stiffness of the matrix fibers. A recent computational model (Zaman et al., 2005) has predicted that these factors are interlinked and affect migration at multiple levels, for example modulation of ligand density affects pore size, matrix stiffness, and forces generated at the cell–matrix interface.

To understand how these factors are convolved, we investigate here the migration of DU-145 human prostate carcinoma cells, both parental and EGF receptor (EGFR)-overexpressors, through 3D fibronectin-constituted Matrigel environments. We observe seemingly paradoxical effects of blocking integrin/matrix adhesion using anti-integrin antibodies as the Matrigel density and concentration of added fibronectin are varied, contrasting with expectations from previous understanding for 2D systems. However, our previously undescribed observations can be accounted for in terms of a force-based computational model for cell migration in 3D matrices (Zaman et al., 2005).


Thorough analysis of their experimental data suggested that migrating cells were unable to “squeeze” through micrometer-sized pores in the matrigel. Instead, tumor cells required proteolysis of the sterically-hindering environment, as well as deformation of the extracellular matrix components, to create open spaces to move through. Because of this, matrix stiffness blocked migration, as opposed to promoting it, as has been seen in 2D cell culture.

The strong similarity between 2D and 3D, however, was in the role of integrin receptor expression and activity. In both cases, a biphasic relationship was found – overexpression resulted in strong adhesions that prevented motility, and underexpression resulted in insufficient traction forces to allow for movement. What might be worth following up, however, is how the structural differences between 2D and 3D relate to observed differences in protein function in focal adhesions and in the actin cytoskeleton. These differences may be due to the stress fibres observed in 2D culture, but to my recollection, the explanation for this remains vague.

References:

  • Migration of tumor cells in 3D matrices is governed by matrix stiffness along with cell-matrix adhesion and proteolysis. Zaman MH, Trapani LM, Siemeski A, Mackellar D, Gong H, Kamm RD, Wells A, Lauffenburger DA, Matsudaira P. Proc Natl Acad Sci U S A. 2006 Jul 10; [Epub ahead of print]. Pubmed.
  • Computational model for cell migration in three-dimensional matrices. Zaman MH, Kamm RD, Matsudaira P, Lauffenburger DA. Biophys J. 2005 Aug; 89(2):1389-97. Pubmed.

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