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Published online 13 January 2003. doi:10.1083/jcb.200209006
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© The Rockefeller University Press, 0021-9525/2003/1/267 $5.00
The Journal of Cell Biology, Volume 160, Number 2, 267-277

Article

Compensation mechanism in tumor cell migration

: mesenchymal–amoeboid transition after blocking of pericellular proteolysis



Katarina Wolf1, Irina Mazo2, Harry Leung3, Katharina Engelke3, Ulrich H. von Andrian4, Elena I. Deryugina5, Alex Y. Strongin5, Eva-B. Bröcker1 and Peter Friedl1

1 Department of Dermatology, University of Würzburg, 97080 Würzburg, Germany
2 Department of Pediatrics, Children's Hospital
3 Department of Pathology, Harvard Medical School, Boston, MA 02115
4 Center for Blood Research, Harvard Medical School, Boston, MA 02115
5 The Burnham Institute, La Jolla, CA 92037

Address correspondence to P. Friedl, Department of Dermatology, University of Würzburg, Josef-Schneider-Str. 2, 97080 Würzburg, Germany. Tel.: 49-931-20126737. Fax: 49-931-20126700. E-mail: peter.fr{at}mail.uni-wuerzburg.de

Invasive tumor dissemination in vitro and in vivo involves the proteolytic degradation of ECM barriers. This process, however, is only incompletely attenuated by protease inhibitor–based treatment, suggesting the existence of migratory compensation strategies. In three-dimensional collagen matrices, spindle-shaped proteolytically potent HT-1080 fibrosarcoma and MDA-MB-231 carcinoma cells exhibited a constitutive mesenchymal-type movement including the coclustering of ß1 integrins and MT1–matrix metalloproteinase (MMP) at fiber bindings sites and the generation of tube-like proteolytic degradation tracks. Near-total inhibition of MMPs, serine proteases, cathepsins, and other proteases, however, induced a conversion toward spherical morphology at near undiminished migration rates. Sustained protease-independent migration resulted from a flexible amoeba-like shape change, i.e., propulsive squeezing through preexisting matrix gaps and formation of constriction rings in the absence of matrix degradation, concomitant loss of clustered ß1 integrins and MT1-MMP from fiber binding sites, and a diffuse cortical distribution of the actin cytoskeleton. Acquisition of protease-independent amoeboid dissemination was confirmed for HT-1080 cells injected into the mouse dermis monitored by intravital multiphoton microscopy. In conclusion, the transition from proteolytic mesenchymal toward nonproteolytic amoeboid movement highlights a supramolecular plasticity mechanism in cell migration and further represents a putative escape mechanism in tumor cell dissemination after abrogation of pericellular proteolysis.

Key Words: cell migration; invasion; fibrosarcoma cells; carcinoma cells; matrix proteases


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