Limits...
Compensation mechanism in tumor cell migration: mesenchymal-amoeboid transition after blocking of pericellular proteolysis.

Wolf K, Mazo I, Leung H, Engelke K, von Andrian UH, Deryugina EI, Strongin AY, Bröcker EB, Friedl P - J. Cell Biol. (2003)

Bottom Line: 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 beta 1 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Dermatology, University of Würzburg, 97080 Würzburg, Germany.

ABSTRACT
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 beta 1 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 beta 1 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.

Show MeSH

Related in: MedlinePlus

Sustained migration in the presence of protease inhibitor cocktail. (A) Cell tracking analysis of the steady-state population speed ± SD and (B) mean speed for each individual cell (time, 20 h; n = 3 experiments, 120 cells).
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2172637&req=5

fig3: Sustained migration in the presence of protease inhibitor cocktail. (A) Cell tracking analysis of the steady-state population speed ± SD and (B) mean speed for each individual cell (time, 20 h; n = 3 experiments, 120 cells).

Mentions: Unexpectedly, although inhibition of collagenolysis by protease inhibitor cocktail was near complete, the migration efficiency of HT-1080/MT1 cells within 3D collagen lattices was barely reduced (Fig. 3). Persistent migration was monitored by sensitive real-time analysis of time-dependent population speed (Fig. 3 A) and the median speed derived from single cell analysis (Fig. 3 B). Similar high migration rates were obtained by BB-2516 alone as well as from HT-1080/neo and wild-type cells in the presence of inhibitor cocktail (unpublished data). Because the capacity to move, i.e., to generate traction and overcome physical matrix constraints appeared intact after blocking of collagenolysis, we hypothesized the existence of compensation strategies to counterbalance the loss of pericellular proteolysis.


Compensation mechanism in tumor cell migration: mesenchymal-amoeboid transition after blocking of pericellular proteolysis.

Wolf K, Mazo I, Leung H, Engelke K, von Andrian UH, Deryugina EI, Strongin AY, Bröcker EB, Friedl P - J. Cell Biol. (2003)

Sustained migration in the presence of protease inhibitor cocktail. (A) Cell tracking analysis of the steady-state population speed ± SD and (B) mean speed for each individual cell (time, 20 h; n = 3 experiments, 120 cells).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2172637&req=5

fig3: Sustained migration in the presence of protease inhibitor cocktail. (A) Cell tracking analysis of the steady-state population speed ± SD and (B) mean speed for each individual cell (time, 20 h; n = 3 experiments, 120 cells).
Mentions: Unexpectedly, although inhibition of collagenolysis by protease inhibitor cocktail was near complete, the migration efficiency of HT-1080/MT1 cells within 3D collagen lattices was barely reduced (Fig. 3). Persistent migration was monitored by sensitive real-time analysis of time-dependent population speed (Fig. 3 A) and the median speed derived from single cell analysis (Fig. 3 B). Similar high migration rates were obtained by BB-2516 alone as well as from HT-1080/neo and wild-type cells in the presence of inhibitor cocktail (unpublished data). Because the capacity to move, i.e., to generate traction and overcome physical matrix constraints appeared intact after blocking of collagenolysis, we hypothesized the existence of compensation strategies to counterbalance the loss of pericellular proteolysis.

Bottom Line: 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 beta 1 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Dermatology, University of Würzburg, 97080 Würzburg, Germany.

ABSTRACT
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 beta 1 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 beta 1 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.

Show MeSH
Related in: MedlinePlus