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

Cellular mechanism of nonproteolytic movement within 3D collagen matrix and related changes in β1 integrin, MT1-MMP, and F-actin distribution in HT-1080/MT1 cells. (A) Induced amoeboid migration lacking fiber degradation. Alignment of cell body along a fiber strand (white arrowheads) and intact individual collagen fiber at its original position after cell detachment (black arrowhead). (B) Migratory alignment of the cell depicted in A along the preexisting fiber scaffold. The outline of the cell edge at 2.5-min time intervals (blue lines) was superimposed onto the 3D reconstruction of the transmigrated matrix structure. Bright pixels indicate colocalization of cell boundary and fibers (arrowheads). (C) Migration through a narrow gap bordered by fibers (black arrowhead) resulting in morphological adaptation and the formation of a constriction ring. (D) Reduced F-actin and β1 integrin focalization at fiber binding sites in an amoeboid HT1080/MT1 cell, compared with F and Fig. 1 C. Because of constriction caused by a perpendicular collagen fiber, this cell contains a lobulated main body. Black arrowhead, uropod. (E) Loss of clustered MT1-MMP and β1 integrins from interactions with fibers in induced amoeboid migration. Arrowheads indicate two simultaneous constriction rings bordered by perpendicular collagen fibers. (F) F-actin and β1 integrins in an untreated control cell of elongated shape. Time: (A) 35 min; (B) 65 min; (C) 20 min. Bars, 20 μm. Black arrows, direction of migration.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2172637&req=5

fig5: Cellular mechanism of nonproteolytic movement within 3D collagen matrix and related changes in β1 integrin, MT1-MMP, and F-actin distribution in HT-1080/MT1 cells. (A) Induced amoeboid migration lacking fiber degradation. Alignment of cell body along a fiber strand (white arrowheads) and intact individual collagen fiber at its original position after cell detachment (black arrowhead). (B) Migratory alignment of the cell depicted in A along the preexisting fiber scaffold. The outline of the cell edge at 2.5-min time intervals (blue lines) was superimposed onto the 3D reconstruction of the transmigrated matrix structure. Bright pixels indicate colocalization of cell boundary and fibers (arrowheads). (C) Migration through a narrow gap bordered by fibers (black arrowhead) resulting in morphological adaptation and the formation of a constriction ring. (D) Reduced F-actin and β1 integrin focalization at fiber binding sites in an amoeboid HT1080/MT1 cell, compared with F and Fig. 1 C. Because of constriction caused by a perpendicular collagen fiber, this cell contains a lobulated main body. Black arrowhead, uropod. (E) Loss of clustered MT1-MMP and β1 integrins from interactions with fibers in induced amoeboid migration. Arrowheads indicate two simultaneous constriction rings bordered by perpendicular collagen fibers. (F) F-actin and β1 integrins in an untreated control cell of elongated shape. Time: (A) 35 min; (B) 65 min; (C) 20 min. Bars, 20 μm. Black arrows, direction of migration.

Mentions: Consistent with impaired collagenolysis, amoeboid moving HT-1080/MT1 cells did not cause structural remodeling of collagen fibers (Video 6, available online at http://www.jcb.org/cgi/content/full/jcb.200209006/DC1). Induced protease-independent migration resulted from adaptation and alignment of the cell body along preformed fiber strands (Fig. 5 A, white arrowheads) and consecutive migratory guidance along fibrillar scaffolds (Fig. 5 B, black arrowheads). Upon cell detachment, no remodeling, bundling, or destruction of the collagen network was generated, leaving behind the intact reticular texture of individual fibrils at their original position (Fig. 5 A, black arrowheads; Video 6). To overcome regions of narrow space by changing shape, an initial pseudopod elongation through a preformed matrix gap (4 μm pore diameter from the central section, 18 μm cell diameter; Fig. 5 C, black arrowhead) was followed by propulsion of the cell body and the development of a narrow region confined by matrix fibers (constriction ring; Lewis, 1934; Fig. 5 C, black arrowhead). Constriction rings persisted until the cell body had squeezed or pulled forward, while no matrix defect was apparent after cell detachment (Fig. 5 C; Video 7, available at http://www.jcb.org/cgi/content/full/jcb.200209006/DC1).


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)

Cellular mechanism of nonproteolytic movement within 3D collagen matrix and related changes in β1 integrin, MT1-MMP, and F-actin distribution in HT-1080/MT1 cells. (A) Induced amoeboid migration lacking fiber degradation. Alignment of cell body along a fiber strand (white arrowheads) and intact individual collagen fiber at its original position after cell detachment (black arrowhead). (B) Migratory alignment of the cell depicted in A along the preexisting fiber scaffold. The outline of the cell edge at 2.5-min time intervals (blue lines) was superimposed onto the 3D reconstruction of the transmigrated matrix structure. Bright pixels indicate colocalization of cell boundary and fibers (arrowheads). (C) Migration through a narrow gap bordered by fibers (black arrowhead) resulting in morphological adaptation and the formation of a constriction ring. (D) Reduced F-actin and β1 integrin focalization at fiber binding sites in an amoeboid HT1080/MT1 cell, compared with F and Fig. 1 C. Because of constriction caused by a perpendicular collagen fiber, this cell contains a lobulated main body. Black arrowhead, uropod. (E) Loss of clustered MT1-MMP and β1 integrins from interactions with fibers in induced amoeboid migration. Arrowheads indicate two simultaneous constriction rings bordered by perpendicular collagen fibers. (F) F-actin and β1 integrins in an untreated control cell of elongated shape. Time: (A) 35 min; (B) 65 min; (C) 20 min. Bars, 20 μm. Black arrows, direction of migration.
© Copyright Policy
Related In: Results  -  Collection

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

fig5: Cellular mechanism of nonproteolytic movement within 3D collagen matrix and related changes in β1 integrin, MT1-MMP, and F-actin distribution in HT-1080/MT1 cells. (A) Induced amoeboid migration lacking fiber degradation. Alignment of cell body along a fiber strand (white arrowheads) and intact individual collagen fiber at its original position after cell detachment (black arrowhead). (B) Migratory alignment of the cell depicted in A along the preexisting fiber scaffold. The outline of the cell edge at 2.5-min time intervals (blue lines) was superimposed onto the 3D reconstruction of the transmigrated matrix structure. Bright pixels indicate colocalization of cell boundary and fibers (arrowheads). (C) Migration through a narrow gap bordered by fibers (black arrowhead) resulting in morphological adaptation and the formation of a constriction ring. (D) Reduced F-actin and β1 integrin focalization at fiber binding sites in an amoeboid HT1080/MT1 cell, compared with F and Fig. 1 C. Because of constriction caused by a perpendicular collagen fiber, this cell contains a lobulated main body. Black arrowhead, uropod. (E) Loss of clustered MT1-MMP and β1 integrins from interactions with fibers in induced amoeboid migration. Arrowheads indicate two simultaneous constriction rings bordered by perpendicular collagen fibers. (F) F-actin and β1 integrins in an untreated control cell of elongated shape. Time: (A) 35 min; (B) 65 min; (C) 20 min. Bars, 20 μm. Black arrows, direction of migration.
Mentions: Consistent with impaired collagenolysis, amoeboid moving HT-1080/MT1 cells did not cause structural remodeling of collagen fibers (Video 6, available online at http://www.jcb.org/cgi/content/full/jcb.200209006/DC1). Induced protease-independent migration resulted from adaptation and alignment of the cell body along preformed fiber strands (Fig. 5 A, white arrowheads) and consecutive migratory guidance along fibrillar scaffolds (Fig. 5 B, black arrowheads). Upon cell detachment, no remodeling, bundling, or destruction of the collagen network was generated, leaving behind the intact reticular texture of individual fibrils at their original position (Fig. 5 A, black arrowheads; Video 6). To overcome regions of narrow space by changing shape, an initial pseudopod elongation through a preformed matrix gap (4 μm pore diameter from the central section, 18 μm cell diameter; Fig. 5 C, black arrowhead) was followed by propulsion of the cell body and the development of a narrow region confined by matrix fibers (constriction ring; Lewis, 1934; Fig. 5 C, black arrowhead). Constriction rings persisted until the cell body had squeezed or pulled forward, while no matrix defect was apparent after cell detachment (Fig. 5 C; Video 7, available at http://www.jcb.org/cgi/content/full/jcb.200209006/DC1).

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