cell news 2/2013
36
physics of cancer
external and internal forces regulate
the transendothelial migration and invasion
of cancer cells from solid tumors
claudia tanja Mierke
Introduction
The motility of cancer cells from solid tumors into the extracellu-
lar matrix of connective tissue has long been investigated by ge-
netic expression profling and mutational analysis. This screening
has been focused on the analysis of genetic alterations affecting
cell-matrix and cell-cell adhesion molecules, focal adhesion pro-
teins, cytoskeletal proteins and their signaling pathways during
the progression of cancer disease and has revealed numerous of
candidate genes playing a role in cancer. In particular these can-
didate genes have been obtained by comparing gene expression
profles of invasive and non-invasive cancer cells. Indeed, many
proteins have been identifed to play a role in cancer cell inva-
sion, transendothelial cell migration and hence tumorigenicity
depending on the specifc cancer type. However, a clear, unique
picture of cancer progression is still elusive. At this point, bio-
physics has been introduced into cancer research and revealed
that biomechanical properties of cancer cells may play a role in
cancer progression and in particular in cancer cell invasion and
transendothelial migration (1-6). The biomechanical properties
of the external microenvironment of neoplasms and tumors as
well as the internal mechanical properties of the cancer cells
can affect and regulate the invasiveness of cancer cells into the
extracellular matrix microenvironment and the transendothelial
migration into blood or lymph vessels (Figure 1). In more detail, it
has been suggested that biomechanical properties of cancer cells
such as the transmission and generation of contractile forces is
determined by the altered mechanical properties of the tumor
microenvironment compared to “healthy” normal tissue. Hence,
the analysis of the biomechanical properties of the local tumor
microenvironment such as the extracellular matrix and embed-
ded neighboring non-cancer cells such as endothelial cells has
become a main focus of biophysically based cancer research.
Besides external forces, internal forces of cancer cells regulate
the invasiveness and the transendothelial migration of cancer
cells. These internal forces may result from cytoplasmic restruc-
turing of the cell`s cytoskeleton for example by breaking cova-
lent-bonds or van der Waals interactions, forming new actin or
keratin polymers or establishing new connections. For example,
the focal adhesion protein vinculin has been shown to be in-
volved in the regulation of contractile forces as well as the cell
surface receptors such as the integrin
α
5
β
1 and the glycosyl
phosphatidylinositol anchored transmembrane protein CD24 re-
gulate the transmission of contractile forces (7-10). Many cel-
lular functions such as cell cycle progression, cell survival, and
migration of cells have been associated with biomechanical pro-
perties demonstrating the importance of biomechanics in the
feld of cell biology, molecular biology and biochemistry. Thus,
this article discusses how the external forces applied to both
normal and cancer cells as well as internal forces of cancer cells
determine their invasiveness into extracellular matrices or their
transendothelial migration effciency. Finally, this article high-
lights by addressing the impact of the regulation of external mi-
croenvironmental forces generated by the extracellular matrix or
external forces exerted by neighboring endothelial cells on can-
cer cells, which then change the cancer cell’s cellular biomecha-
nics, and subsequently the cancer cell’s motility or invasiveness
and cancer cell’s ability to cross endothelial borders.
External forces regulate the behavior of cancer cells
The invasiveness of cancer cells depends not only on a single
biomechanical or biochemical parameter, it rather depends on
the balance of several parameters that act together to facilitate
cell invasion and transendothelial migration. In particular, the
stiffness or softness of cancer cells infuences together with the
cytoskeletal remodeling dynamics and the transmission or gene-
ration of contractile forces the invasiveness of cancer cells into
3D extracellular matrices (2, 5, 8).
Forces exerted by the extracellular matrix
The microenvironment of cells in tissues differs in their com-
position, steric hindrance (pore-size, bending stiffness, fber
