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The Interplay of Cell-Cell and Cell-Matrix Interactions in the Invasive Properties of Brain Tumors

Balázs Hegedüs ^* , Françoise Marga ^*, Károly Jakab ^*, Kathy L. Sharpe-Timms  and Gabor Forgacs ^* 

^* Department of Physics, University of Missouri, Columbia, Missouri 65211; National Institute of Neurosurgery, Budapest, Hungary H-1145; Department of Obstetrics, Gynecology and Women's Health, University of Missouri, Columbia, Missouri 65211; and Department of Biology, University of Missouri, Columbia, Missouri 65211

Correspondence: Address reprint requests to Gabor Forgacs, Dept. of Physics and Dept. of Biology, University of Missouri, Columbia, MO 65211. E-mail: forgacsg{at}missouri.edu.

Impairment of tissue cohesion and the reorganization of the extracellular matrix are crucial events during the progression toward invasive cell phenotype. We studied the in vitro invasion patterns of nine brain tumor cell lines in three-dimensional collagen gels. Cell-cell and cell-matrix interactions were quantified and correlated with the expression level of specific molecules: N-cadherin, matrix metalloproteinases, and their inhibitor. Pattern evolution was studied as a function of time and collagen concentration. Cells with low metalloproteinase expression or high tissue cohesion showed limited invasive potential. Higher metalloproteinase expression and intermediate tissue cohesion resulted in configurations with hypercellular zones surrounding regions mostly devoid of cells and with digested collagen, akin to pseudopalisades in surgically removed malignant astrocytoma specimens. In physical terms, these configurations arise as the result of competition between cell-cell and cell-matrix interactions. Our findings suggest specific ways to characterize, control, or engineer cell migratory patterns and hint at the importance of the interplay between biophysical and biomolecular factors in the characterization of invasive cell behavior and, more generally, in epithelial-mesenchymal transitions.