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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.

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Concept on mesenchymal–amoeboid transition. A program of morphodynamic and molecular changes after abrogation of pericellular proteolysis by protease inhibitors provides a supramolecular mechanism for persistent nonproteolytic migration in 3D fibrillar collagenous tissues.
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fig7: Concept on mesenchymal–amoeboid transition. A program of morphodynamic and molecular changes after abrogation of pericellular proteolysis by protease inhibitors provides a supramolecular mechanism for persistent nonproteolytic migration in 3D fibrillar collagenous tissues.

Mentions: Inhibition of constitutive proteolysis, instead of causing the cells to become “trapped” within the fibrillar network, induced a program of morphodynamic and molecular changes that allowed the maintenance of the migratory action (Fig. 7). These changes included a reduced elongation yet increased morphodynamic flexibility, the loss of focal β1 integrin and MT1-MMP clustering at interactions with matrix fibers, and a more diffuse cortical actin distribution, including small actin-rich nucleation foci at fiber binding sites. These features are coupled to the forward flow (streaming) of cytoplasm through cell regions of narrow space confined by outside constriction and, together, result in a phenotype mimicking amoeboid moving cells (Yumura et al., 1984; Devreotes and Zigmond, 1988; Killich et al., 1993; Friedl et al., 2001). Because this induced amoeboid behavior generated significant migratory activity, yet the transmigrated collagen architecture remained intact by means of biochemical and structural analysis, our data show an alternative inhibitor-induced nonproteolytic migration type (Fig. 7).


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)

Concept on mesenchymal–amoeboid transition. A program of morphodynamic and molecular changes after abrogation of pericellular proteolysis by protease inhibitors provides a supramolecular mechanism for persistent nonproteolytic migration in 3D fibrillar collagenous tissues.
© Copyright Policy
Related In: Results  -  Collection

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

fig7: Concept on mesenchymal–amoeboid transition. A program of morphodynamic and molecular changes after abrogation of pericellular proteolysis by protease inhibitors provides a supramolecular mechanism for persistent nonproteolytic migration in 3D fibrillar collagenous tissues.
Mentions: Inhibition of constitutive proteolysis, instead of causing the cells to become “trapped” within the fibrillar network, induced a program of morphodynamic and molecular changes that allowed the maintenance of the migratory action (Fig. 7). These changes included a reduced elongation yet increased morphodynamic flexibility, the loss of focal β1 integrin and MT1-MMP clustering at interactions with matrix fibers, and a more diffuse cortical actin distribution, including small actin-rich nucleation foci at fiber binding sites. These features are coupled to the forward flow (streaming) of cytoplasm through cell regions of narrow space confined by outside constriction and, together, result in a phenotype mimicking amoeboid moving cells (Yumura et al., 1984; Devreotes and Zigmond, 1988; Killich et al., 1993; Friedl et al., 2001). Because this induced amoeboid behavior generated significant migratory activity, yet the transmigrated collagen architecture remained intact by means of biochemical and structural analysis, our data show an alternative inhibitor-induced nonproteolytic migration type (Fig. 7).

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