Biomedical Engineering Reference
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between the membranes in the contact zone of the interacting cells. The expression
levels of b-catenin (denoted by [b]) can be used to determine a cell's migration
potential by comparing with a threshold. Specifically, if [b] exceeds the threshold,
the soluble b-catenin in cytoplasm is considered to be large enough, so it is free to
enter the nucleus and interact with transcription factors, resulting in cell migration.
Note that, the decision for a cell to migrate can be triggered in a number of
different ways, all of them involving an upregulation of the soluble b-catenin
which needs to exceed the pre-specified threshold. For example, the cytoplasmic
concentration of b-catenin may be upregulated due to a failure in the proteasome
system or detachment of local neighbors; in both cases, free b-catenin enters the
nucleus and triggers cell migration.
2.2.4 Modeling Examples
A number of computational studies have been carried out to probe the relative
importance of E-cadherin and b-catenin intracellular signaling properties in
determining tumor tissue characteristics. A multiscale lattice-free ABM was first
developed to study how cell adhesion may be regulated by the interactions
between E-cadherin and b-catenin [
48
]. Simulation results showed that down-
regulation of b-catenin can be mainly driven by cell-cell contacts, and EMT can
be achieved depending on the regulation of soluble b-catenin by local contacts.
The intra- and intercellular protein interactions that govern cell-cell adhesion
combined with cellular physical properties are also the driving forces of an
essential mechanism that a cancer cell uses to attach to the endothelial wall, i.e.,
transendothelial migration (TEM) [
52
]. In a subsequent study [
47
], the influence
of different protein pathways in the achievement of TEM was investigated by
adding the Src pathway to the molecular layer. Four cancer cell genotypes that
differ in the adhesion protein pathways were considered. The genotypes were
characterized by their capacity of creating N-cadherin-mediated bonds with the
tunica intima and by their capacity of inducing a detachment of the endothelial-
endothelial bonds by Src activity. Simulation results indicate that the slowest
migration was found in the case when both N-cadherin and Scr were knocked
out, while the fastest case occurred when both N-cadherin and Scr remained
active.
In a more recent study from the same group [
44
], three cell-cell adhesion sub-
pathways were proposed, and the influence of these pathways on tumor profiles
was studied. Sub-pathway 1 considers bond formation as a cause of the interaction
between b-catenin and E-cadherin; sub-pathway 2 considers in addition the deg-
radation of the adhesion complex after b-catenin is phosphorylated by Src; and
sub-pathway 3 considers intracellular interactions between Src, b-catenin,
E-cadherin, and PI3. Model analysis finds that cells with sub-pathway 2 and slow
synthesis rate of Src associated sub-pathway 3 generated the largest subpopulation
due to an advantageous position close to the tumor border that permits them to
more easily form clones of large size. Figure
3
shows the transversal section of
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