Biomedical Engineering Reference
In-Depth Information
the initial tumor site in a process called metastasis is responsible for spreading
the malignancy to additional sites in the body.
In vivo
, animal cells crawl within a tissue among other cells and extracel-
lular matrix material in either a 2D or 3D environment.
In vitro
, cell motility
is most often studied by plating cells on a 2D artificial substrate such as a
glass coverslip. To crawl across a substrate, a cell must coordinate four mech-
anistically distinct processes in both space and time: protrusion of the leading
edge, adhesion to the substrate, forward translocation of the cell body, and
retraction of the rear [1, 2]. The migrating cell must be highly polarized so
that these distinct processes can be localized to different regions of the cell.
The majority of animal cells, as well as many unicellular organisms, move by
actin-based crawling, in which protrusion at the leading edge is powered by
polymerization of polar actin filaments that assemble into a dense dendritic
network. Specific molecular components are required for the dynamic assem-
bly of this cytoskeletal network, including factors that nucleate growth of new
actin filaments, cross-link filaments, and catalyze filament disassembly. The
actin cytoskeleton is anchored to the substrate through a complicated array
of adhesion molecules (reviewed in [3, 4]), and this attachment enables the
force generated by actin polymerization to be translated into cell protrusion.
This general mechanism of actin-based motility is conserved from protozoa
through vertebrates.
Research in the last few decades has focused on uncovering the biochemical
basis of cell motility, and indeed numerous biochemical, structural, and genetic
studies are now converging into an overall picture of the order of events and
identities of the major molecular players involved in cell motility (reviewed in
[3, 5, 6, 7]). With the characterization of the molecular basis of cell motility
well underway, a new challenge has come to the fore: understanding how the
cell coordinates the enormous number of molecules involved to achieve robust
whole-cell motility that can be intrinsically persistent over time scales that are
very long compared to the dynamics of individual protein-protein interactions,
and yet remain responsive to changes in the mechanical and chemical features
of its environment. A great deal of recent work in the field has focused on
the cell-signaling mechanisms involved in the establishment and maintenance
of large-scale cell polarity (reviewed in [8]). Less attention has been given
to the equally important mechanical and physical aspects of the large-scale
coordination of cell dynamics.
The importance of the interplay between molecular processes and me-
chanical and physical characteristics of the system are well illustrated by the
actin-based motility of the intracellular bacterial pathogen
Listeria monocy-
togenes
. This pathogen hijacks the host cell's actin machinery and forms an
actin “comet tail” which it uses to propel itself within the cell and through the
membrane into neighboring cells, allowing ecient infection of a large num-
ber of cells without encountering the immune system. This form of motility
depends solely on protrusion by actin polymerization, and unlike whole-cell
motility, does not involve adhesion or contraction.
Listeria
motility was recon-
