Biomedical Engineering Reference
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Fig. 2 The effects of asynchronous combinatorial change in EGF and TGFb concentrations on
tumor volume represented by cell number (left panel) and tumor expansion rate represented by
inverse simulation step (right panel). In tumor volume evaluation, the largest tumor volume is
reached under conditions of high TGFb and low or standard (with a variation of 1.0-fold) EGF
concentrations. However, in tumor expansion rate evaluation, the most aggressive tumor
expansion rate (fewest simulation steps) occurs under conditions of high EGF, regardless of
TGFb concentrations. Reproduced with permission from [
43
]
within this region, changes caused by the two growth factors did not effectively
transmit to the downstream activation cascade, potentially explaining the resulting
robustness of the tumor system at the multi-cellular level. However, the tumor
system becomes sensitive to external variations in EGF and/or TGFb when they
occur outside this region, processing a phenotypic switch once the microenviron-
ment becomes more permissive.
2.2 E-cadherin Signaling and Cell-Cell Adhesion
E-cadherin mediates cell-cell adhesion and plays a critical role in the formation
and maintenance of cell contact. E-cadherin mutation has been correlated with
malignant transformation and invasive behavior [
45
], whereas increasing the
E-cadherin expression level has been shown to reduce the growth of malignant cell
lines [
46
]. Only recently, cancer modelers began to explicitly investigate cell-cell
adhesion related intracellular signaling in a multicellular context to understand the
possible effects of changes in E-cadherin on the growth characteristics of cancer
cell populations [
44
,
47
,
48
].
2.2.1 E-cadherin Signaling
When a cell adheres to adjacent neighbors, E-cadherin binds to b-catenin to form a
complex which can interact with neighboring cells to form bonds. When cells
detach from one another, b-catenin is released into the cytoplasm, targeted for
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