cell news 2/2013
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physics of cancer
ting cell contraction, extension and translocation in a specifc
direction (depending on external signals) (18-19). As a cancer
cell moves on or in the extracellular matrix, it experiences ex-
ternal forces, which include the viscous force or resistance from
the surrounding matrix and cell-substrate interaction forces, i.e.
adhesion forces, and internal forces, i.e. cytoskeletal forces that
are generated by the cytoskeleton. As forces are applied through
adhesion molecules towards the microenvironment, cells con-
tinuously respond by exerting reciprocal contractile forces to
external forces, which are applied to cancer cells by the extra-
cellular matrix and surrounding neighboring cells (18). Finally,
the anisotropy of the cell’s adhesive microenvironment such as
the mechanical forces controls the intracellular cytoskeletal or-
ganization and facilitates the polarity of the cell (20) and sub-
sequently regulates the invasiveness or transmigration ability of
cells in 3D extracellular matrices.
Forces exerted by other neighboring cells within the extra-
cellular matrix
Some years ago the “biochemical” role of endothelial cells in
metastasis was established and well defned: the endothelium
fulflls the role of a passive barrier avoiding cancer cell invasion
and spreading into the blood or lymph vessels (21-22). However,
this view changed dramatically in 2008: Since then it is wide-
ly accepted that endothelial cells fulfll a novel function during
cancer metastasis by facilitating and increasing the invasion of
certain “aggressive” cancer cell lines into 3D extracellular mat-
rices (2). Indeed, this fnding challenged the view of the endo-
thelium from a passive barrier restricting cancer cell invasion
in general to the view of the endothelium acting as an active
modulator or enhancer of the invasion of specifc cancer cell
types (2). However, there are still unsolved steps in metastasis
and open questions: Do endothelial exerted mechanical forces
regulate the transmigration of cancer cells? Do transmigrating
cancer cells sense the mechanical alterations evoked by endo-
thelial cells? What roles play guiding cells such as tumor-associ-
ated macrophages in the mechano-regulatory scenario? How do
cancer cells that circulate in the blood stream manage to adhere
to the endothelium and transmigrate through it? Do cancer cells
circulating in vessels use similar mechanisms as leucocytes to
transmigrate through the endothelial lining?
However, the transmission and generation of contractile forces
by cancer cells are involved in the process of invasion and tran-
sendothelial migration. It has been shown that the contracti-
le actomyosin apparatus of adjacent endothelial cells supports
the invasiveness of cancer cells (23). Until now it is still elusive
whether the intermediate flament cytoskeleton and the micro-
tubule cytoskeleton are involved in transmitting and generating
contractile forces to enhance the effect of the actomyosin cy-
toskeleton. As invasive cancer cells alter the mechanical proper-
ties of adjacent endothelial cells, in turn, endothelial cells may
alter the mechanical properties of cancer cells to enable them
to transmigrate through. How does this interaction take place?
Do endothelial cells induce forces to adhering cancer cells? How
does the adhesion of invasive and non-invasive cancer cells alter
the exerted mechanical forces from the underlying endothelium?
Internal forces regulate cellular functions of cancer
cells
Forces can be generated by the actomyosin cytoskeleton of cells
and are important in regulating cellular motility through extra-
cellular matrices and the endothelium. By coordinating the enti-
re process of cell locomotion precisely, the cytoskeleton consists
of a polymer network including the three main cytoskeletal fla-
ments: actin flaments (microflaments), intermediate flaments
and microtubules. The flaments represent polymers with diffe-
rent mechanical properties such as stiffness or rigidity, which is
given by the persistence length of the biopolymers. The persis-
tence length is a basic mechanical property which quantifes the
stiffness of a polymer and can be expressed using bending stiff-
ness (the Young’s modulus). In particular, the persistence length
is defned as the end-to-end distance vector over which the f-
lament can be bent by applying thermal forces. If the stiffness
of a polymer increases, the persistence length increases similarly
(24).
Forces generated by the actin cytoskeleton
The primary step of starting the motility of cancer cells is the
protrusion formation of the leading edge in the direction of the
motion. The extension of the leading edge of migrating cells is
a multi-step process, which is a precisely regulated complex
scenario (25-32). The underlying mechanism of building protru-
sions is the active polymerization of actin flaments towards the
cell membrane at the leading edge that pushes the membrane
straight forward in the direction of motion or invasion. Howe-
ver, the polymerizing actin flaments are not able to transmit or
generate contractile forces: without any accompanying myosin
motors, cells are not able to generate strong forces to mediate
the movement of a cell's leading edge. In more detail, an actin
flament is not a stiff rod, which stops growing once when re-
aching the cell membrane. Instead, actin is an elastic flament,
which is bent after applying loads or forces, and it may insert its-
elf through the existing actin flament and cell membrane (33).
Subsequently, the lengthened actin flament is able to exert an
elastic force towards the cell membrane in order to push it for-
ward in the direction of movement.
Indeed, actin flaments and extracellular matrix focal adhesions
are needed to omit the backward movement of polymerizing
actin flaments. It still remains an open question: How can an
actin flament polymerize against an external stress such as the
cell membrane or external forces and generate a polymerization
force?
