Deciphering Fate Decision in Normal and Cancer Stem Cells: Mathematical Models and Their Experimental Verification - Mathematical Methods and Models in Biomedicine - page 216

resilient state of a normal tissue as described by the general model. Examination
of how various changes in model parameters affect cell-population size resulted
in significant conclusions: First, accelerated death of DCs weakened the negative
feedback that these cells posed on CSC proliferation, which, rather counter-
intuitively, increased the number of cycling CSCs. This observation is in line with
the CSC hypothesis that to achieve tumor elimination CSCs must be targeted instead
or in addition to the transient amplifying tumor cells [ 78 ]. Second, simulation
results suggested that neither inhibition of proliferation alone nor stimulation of
differentiation alone was sufficient to reduce both cycling and non-cycling CSC
populations. Moreover, the model enabled analysis of the tumor growth dynamics,
and the results implied that the tumor radius grows linearly with time.
Attempting to decipher the mechanism that enables QS, Agur et al. [ 5 ] introduced
a new hybrid CA model, which described processes at the molecular level in
addition to dynamics at the tissue level. The model included a detailed description
of the intracellular system of signaling pathways, triggered by microenvironmental
signals received from neighboring cells, which were found to balance SC replication
and differentiation in developing tissues and in particular in the mammary tissue and
in breast cancer. Analyzing this model enabled the authors to explore the means by
which tissue balance can be controlled. In the case of cancer, this would mean con-
trolling tumor growth. Analysis of this model [ 44 ] pinpointed the Dkk1 protein as a
key factor in breast cancer SC fate decision regulation, as it increases the probability
of SC differentiation, in addition to reducing the probability of its proliferation.
Numerical simulations of the model [ 5 ], corroborated by experiments, suggested
the existence of a critical Dkk1 concentration, below which SC replication remains
largely unaffected. Above this threshold, SC replication is significantly suppressed.
Overall, these models present a new concept, in which QS is viewed as the
basic regulatory mechanism driving SC and CSC fate decision. This mechanism
is the foundation for the maintenance of healthy tissue homeostasis [ 4 , 45 ], and its
disruption is at the source of cancer initiation [ 3 ]. Deciphering the explicit molecular
mechanism that enables SCs to monitor their environment and, thus, to modulate
tissue homeostasis could pave the way to controlling fate decision. In the case of
CSCs, this could lead to identifying new therapeutic agents to be used for controlling
tumor progression, as demonstrated by a model of the network of intracellular
signaling pathways controlling fate decision in breast cancer SCs [ 5 , 44 ].
Recently, there is growing interest in the theory of the stem cell niche , suggesting
that SCs reside in a supporting physiological microenvironment of a defined
structure within the tissue [ 55 ]. The existence of such a niche for CSCs has been
proposed, and experimental evidence for this structure has been found at least
in colon cancer, where SCs seem to be localized in a narrow ring near the base
of the crypts, and in breast cancer (for reviews see [ 14 , 50 , 79 ]). The normal
or cancer SC niche is usually described as a physiological microenvironment,
consisting of specialized cells that provide the necessary conditions for SCs to
remain undifferentiated and proliferate. These supporting niche-cells are thought
to participate in the regulation of SC fate decision and control their range of
function [ 14 ]. However, the QS model presented here shows that the creation