Biomedical Engineering Reference
In-Depth Information
two states: (i) system death, i.e., when all SCs differentiate and eventually die, or (ii)
uncontrolled proliferation, i.e., when most of the SCs keep proliferating and do not
differentiate throughout the duration of the simulation. In the latter case, when the
modeled tissue becomes saturated with cells, the system achieves a quasi-steady-
state, where a small stable fraction of the cell population is DCs, and a much greater
part of the CA is occupied by SCs. Statistical segmentation of all simulation results
showed that the magnitude of intercellular communication, represented by the QS
parameter, dominantly affects the probability of uncontrolled proliferation and the
probability of system death. The conclusion is that tissue homeostatic balance is
highly dependent on signal intensity, which implies that QS is a crucial mechanism
in fate decision.
Analysis and simulations, examining the effect of relations between the kinetic
parameters, show that shortening DC life span can increase the proliferation of
SCs. Analysis also shows that proliferation may become unlimited when the
initial SC population is large. A possible implication for SC therapy would be
a necessity to limit the initial number of implanted SCs. Regarding cancer, these
results are consistent with the CSC theory rationalization that conventional therapy
fails because it mainly eliminates non-CSC tumor cells (as represented in the
simulation of shortening DC life span). Moreover, these results imply that such
therapy may intensify CSC proliferation. Implications of the conceptual QS model
for a cancerous tissue will be discussed in detail in the following section.
5.3
Model of Cancerous Tissue
The existence of the QS mechanism implies that the trigger for cancer may lie in
the SC's ability to sense its microenvironment. The results of the model analysis
described above suggest that excessive cell proliferation may result from changes
in the kinetic parameters of the SCs changing their inherent ability to receive
signals, or from changes in the microenvironment, affecting the magnitude of the
signals transduced to SCs. Hence, cancer initiation may be stimulated by factors
that cause microenvironmental changes (e.g., inflammation) rather than by increased
mutagenesis, as suggested elsewhere [
58
]. On the other hand, a natural outcome of
excessive proliferation is an increase in the expected number of random mutations,
including irreversible oncogenic mutations. If this explanation for carcinogenesis
is valid, it means that in the first stage of cancer development, namely, during
extensive proliferation of normal SCs, carcinogenesis can be reversed by inducing
environmental changes that modify cell signaling intensity.
This also means that the SCs' microenvironment is where we should look
for keys to possibly control, prevent, or reverse the direction of tumor growth.
If we adopt the theory that CSCs are largely responsible for tumor growth, then
controlling the dynamics of cancer progression might become possible through
imposing changes in the environment of these SC-like cells. Drugs affecting local
signals in the interactions between CSCs can be used for manipulating their
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