cell news 2/2013
39
physics of cancer
The actin flaments are semifexible polymers, assembled from
dimer pairs of globular actin, and functionally polar. Thus, actin
flaments have two distinct ends: a fast (plus end) and a slow
growing end (minus end). The minus end of the actin flament
has a critical actin monomer concentration that is approximate-
ly six times higher compared to the plus end actin monomer
concentration. Above its critical concentration, the actin fla-
ment end will bind actin monomers and grow by polymerization.
However, when the concentration of actin monomers is below
the critical concentration, actin monomers detach from the actin
flament end inducing actin flament depolymerization. Due to
these two different critical actin concentrations at the plus and
minus ends of the actin flament, these actin flaments are able
to grow asymmetrically. In particular, when the actin monomer
concentration is in between the two critical actin monomer va-
lues, only the plus end of the actin flaments grows while the
minus end depolymerizes, a situation termed “treadmilling”. This
actin treadmilling process explains how actin flaments can ge-
nerate a polymerization force regulating cell invasion and tran-
sendothelial migration.
Forces generated by the intermediate cytoskeleton
Intermediate flaments have a shorter persistence length com-
pared to actin flaments and hence, are much more fexible than
actin flaments and microtubules. Although there are different
classes of intermediate flaments such as vimentin, desmin, kera-
tins, and lamins, they are in contrast to actin flaments or micro-
tubules not polarized, not able to treadmill and do not normally
depolymerize under physiological conditions upon polymeriza-
tion. Thus, intermediate flaments are more static and less dy-
namic compared to actin flaments or microtubules. How these
intermediate flaments contribute to the mechanical properties
is still under investigation. It is suggested that they even play
an equal important role similar as actin flaments for providing
cellular mechanical properties such as forces.
Forces generated by the microtubule cytoskeleton
Microtubules exhibit the largest persistence length when com-
pared with actin or intermediate flaments and therefore they
are the stiffest of these three biopolymers (34). As actin poly-
mers, microtubules are rod-like polymers. The alpha and beta tu-
bulin protein subunits assemble alternating into protoflaments,
and typically 13 of these protoflaments align together to form
a hollow cylinder providing the strong rigidity or stiffness. Mi-
crotubules possess similar assembly and disassembly dynamics
compared to actin. In more detail, microtubules are polar re-
garding their function, undergo readmilling similar to actin fla-
ments and can generate a force upon polymerization of tubulin
monomers into protoflaments (35). How microtubules contribu-
te to the motility of (cancer) cells is under strong investigation
and may also play a role in macromolecule crowding effects re-
gulating (cancer) cell invasion.
Conclusion
This article focused on the internal forces of cancer cells and on
external forces generated by the extracellular matrix connective
tissue and/ or adjacent endothelial cells and the impact of inter-
nal and external forces on cancer cell invasion and transendo-
thelial migration. Indeed, external and internal forces regulate
many functions of cancer cells such as cell proliferation, apop-
tosis, cell fusion, connective tissue invasion and transendothelial
migration. The understanding of the interplay between cancer
cells and their microenvironment and in particular, the mecha-
nical stimulation of cancer cells through external forces of the
microenvironment such as the extracellular matrix or neighbo-
ring embedded endothelial cells and internal contractile forces
of cancer cells may reveal new mechanically induced pathways
promoting or increasing cancer cell invasion and transmigration
through the endothelium of connective tissue. Finally, the force
transmission and generation of the invasive cancer cells build
the focus of many biophysical approaches studying cancer pro-
gression and the process of metastasis. However, the role of the
endothelial cells in providing external forces regulating cancer
cell transmigration and invasion still needs further investigati-
on. In particular the role of the actin flaments, intermediate
flaments and the microtubules in transmitting and generating
forces are still the focus of current cellular biophysical research.
In summary, our studies provided a novel role of the endotheli-
um in initiating and promoting the invasion of cancer cells and
we therefore postulate a mechanical role for endothelial cells in
regulating cancer cell invasion and transmigration.
Acknowledgement
This work was supported by the Deutsche Krebshilfe (109432) and ESF/SAB (100147954).
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