concentration returns to normal values, the changes can be
maintained [143].
Moreover, the entropy production rate increases when exposed
to higher extracellular glucose concentration in the three pheno-
types (seeFig. 10b).
Taking the glucose concentration like a control parameter and
replacing in Eq. (18), we havedS_i
dt¼∂S_i
∂GlcdGlc
dt< 0 ð 38 ÞThe glucose concentration decreases because it is a reactant,
thus we havedGlc/dt<0; therefore, we must have∂S_i=∂Glc> 0
(seeFig. 10b). It is noted that the production of entropy per unit of
timeS_i, evaluated through Eq. (4), is indicative of the directional
character and stability of the dynamical behavior of cancer
glycolysis [141].
One of the strategies used to fight the cancer has been the
abrupt decrease of glucose concentration in the tumor microenvi-
ronment [134]. Cancer cells that develop accelerated glycolysis due
to activation of oncogenes (including Ras, Her-2, and Akt) or due
to loss of tumor suppressor function (including TCS1/2, p53,
LKB1) undergo rapid apoptosis when placed in culture conditions
with low glucose concentrations [134]. That is observed in
Fig.10b for the three phenotypes.
Therefore, glucose deprivation must be carried out in a shorter
time than required by the tumor cells to acquire a characteristic
phenotype. In this case, the hypoglycemic phenotype which, as
shown in Fig.10a, exhibits a higher entropy production rate, and
consequently will have a greater robustness.
It is known that the glucose deprivation markedly enhances
oxidative stress by increasing the intracellular level of ROS
[122]. ROS acts as a signal transduction messenger and can pro-
mote the proliferation or cellular death of cancer cells, depending
on the intra and extracellular condition of the antioxidant defense
mechanisms.
Cancer cells subjected to persistent endogenous and exogenous
oxidative stress were shown to develop adaptive responses, mainly
related to the upregulation and activation of the antioxidant
machine, that can contribute to cancer progression through an
array of interconnected signals, among them, activation of RAS
oncogen [144].
The bigger robustness of the hypoglycemic phenotype may be
related to the increase of levels of ROS as consequence of low
extracellular glucose concentration, and therefore is related to the
contribution of ROS to the development and cell proliferation. The
cells grown in hypoglycemic conditions could be adapted to a
ROS-resistant phenotype, and this could be maintained even if
the cells were later submitted to a high glucose concentration.Parameters Estimation in Phase-Space Landscape Reconstruction of Cell Fate... 157