The biology of cell locomotion within three-dimensional extracellular matrix

Abstract

Cell migration in three-dimensional (3-D) extracellular matrix (ECM) is not a uniform event but rather comprises a modular spectrum of interdependent biophysical and biochemical cell functions. Haptokinetic cell migration across two-dimensional (2-D) surfaces consists of at least three processes: (i) the protrusion of the leading edge for adhesive cell-substratum interactions is followed by (ii) contraction of the cell body and (iii) detachment of the trailing edge. In cells of flattened morphology migrating slowly across 2-D substrate, contact-dependent clustering of adhesion receptors including integrins results in focal contact and stress fiber formation. While haptokinetic migration is predominantly a function of adhesion and deadhesion events lacking spatial barriers towards the advancing cell body, the biophysics of the tissues require a set of cellular strategies to overcome matrix resistance. Matrix barriers force the cells to adapt their morphology and change shape and/or enzymatically degrade ECM components, either by contact-dependent proteolysis or by protease secretion. In 3-D ECM, in contrast to 2-D substrate, the cell shape is mostly bipolar and the cytoskeletal organization is less stringent, frequently lacking discrete focal contacts and stress fibers. Morphologically large spindle-shaped cells (i.e., fibroblasts, endothelial cells, and many tumor cells) of high integrin expression and strong cytoskeletal contractility utilize integrin-dependent migration strategies that are coupled to the capacity to reorganize ECM. In contrast, a more dynamic ameboid migration type employed by smaller cells expressing low levels of integrins (i.e., T lymphocytes, dendritic cells, some tumor cells) is characterized by largely integrin-independent interaction strategies and flexible morphological adaptation to preformed fiber strands, without structurally changing matrix architecture. In tumor invasion and angiogenesis, migration mechanisms further comprise the migration of entire cell clusters or strands maintaining stringent cell-cell adhesion and communication while migrating. Lastly, cellular interactions, enzyme and cytokine secretion, and tissue remodeling provided by reactive stroma cells (i.e. fibroblasts and macrophages) contribute to cell migration. In conclusion, depending on the cellular composition and tissue context of migration, diverse cellular and molecular migration strategies can be developed by different cell types.

High-Risk Endometrial Carcinoma Profiling Identifies TGF-β1 as a Key Factor in the Initiation of Tumor Invasion

“…These spheres seem to form a cooperating unit with a highly persistent and directional migration type into the 3D matrix. In vivo, clustered migration would minimize cell loss, favor high local MMP expression, and protect cancer cells from immunological assault (35). We hypothesize a stepwise process where TGF-b1 stimulates EMT in the endometrial tumor cells, enabling them to migrate through the porous membrane before the development of the EGF-dependent invasive glandular structures (Fig.…”

Microtubule regulation of corneal fibroblast morphology and mechanical activity in 3-D culture

“…However, cells reside within 3-D extracellular matrices in vivo, and ECM geometry has also been shown to effect cell morphology, mechanical activity, and adhesion organization and composition (Abbott, 2003;Bard and Hay, 1975;Cukierman et al, 2001;Cukierman et al, 2002;Doane and Birk, 1991;Friedl and Brocker, 2000;Grinnell et al, 2003;Tomasek et al, 1982) While it is known that microtubules play a role in cell spreading and contractility within 3-D collagen matrices, these processes have not been assessed dynamically in individual cells. Furthermore, their influence on the subcellular pattern of force generation and local cell-induced matrix reorganization has not been reported previously.…”

Catch of the day: zebrafish as a human cancer model

“…Recent work indicates that mesenchymal migration involves the release of matrix-degrading proteases and matrix digestion, whereas amoeboid migration utilizes dynamic membrane blebbing and cell contractile processes to traverse through existing openings in the surrounding matrix independent of proteases (Friedl and Bro¨cker, 2000;Wolf et al, 2003). The bad news is that metastatic cells may be armed with both modes of invasion and that blocking one mode may not be sufficient to prevent cell dissemination since they can switch to the other mode.…”