Abstract
TNF-related apoptosis-inducing ligand (TRAIL) provokes apoptosis selectively
in cancer cells. Although extensively investigated with experimental
and theoretical approaches, underlying mechanisms explaining the
apoptotic response of a cell population remain unclear. Here, experimental
results concerning populations of lung cancer cell line stimulated
with a superior second generation TRAIL variant are analyzed with
help of appropriate mathematical models. An individual-based framework
describing the dynamics of a cell population in response to the ligand
is developed. Published models of the signaling pathway are integrated
and population parameters are adapted to experimental data. Model
simulations show that initial molecular changes after TRAIL stimulation
are expected in the XIAP protein distribution. A shift in the caspase-8
distribution is predicted to be of capital importance for a transient
insensitivity against TRAIL. Furthermore, it becomes clear that consideration
of inheritance is crucial for the understanding of longterm responses
to stimulations with TRAIL. Interestingly, the comparison of data
and simulations of the population model revealed differences in the
cell cycle dependence of death patterns. Hence, a phenomenological
minimal model is developed in order to verify possible connections
between cell cycle and apoptosis. Longterm time-lapse microscopy
data are used for parameter estimation and model selection. The analysis
gives insights into mechanisms of cell death progression during different
phases of the cell cycle. The presented results are important steps
for the improvement of a predictive model with the objective of optimizing
TRAIL-based cancer therapies.
Users
Please
log in to take part in the discussion (add own reviews or comments).
