D. Kokosi2, G. An1 1University Of Chicago,Surgery,Chicago, IL, USA 2National And Kapodistrian University Of Athens,School Of Medicine,Athens, ATHENS, Greece
Introduction: Gliomagenesis is a phenomenon of complex molecular etiology, with recent genomic screening supporting the importance of telomere biology. There is a suggestion of a the correlation between long telomere length predisposition and increased risk of glioma. The hypothesis that longer telomere length enhances the proliferative capacity of each cell and therefore increases the possibility of malignant transformation is backed by various studies related to different types of carcinogenesis; however, a systemic approach to understanding the dynamics of this correlation is difficult to accomplish in vivo due to the complexity of the constituting factors. Agent-based modeling, a computational modeling method, can be applied to examine hypotheses related to specific elements of gliomagenesis in a dynamic and systemic fashion, and evaluate macroscopic evidence through cell-level systems components and functions. Consequently, we have developed an abstract agent-based model (ABM) that encompasses the fundamental aspects of neural tissue function in healthy and injured states, and incorporated a possible role of telomere length and inflammation in glioma oncogenesis.
Methods: The ABM that was developed includes agents representing neurons, astrocytes, microglia and stem cells. The inter-agent interaction via signaling molecules in both healthy and injured states is based on published mechanisms. The model was calibrated to simulate the generation and accumulation of mutations in astrocytes in relation to their degree of activation during injury response. Important parameters that were incorporated and examined during experimental runs include: activation of glial cells, astrocyte proliferation, lifespan of cells, telomere length and mutation levels of astrocytes, neuron damage and degeneration, inflammation and chemotaxis. Stem cell differentiation was triggered via a counter or due to local injury.
Results: The ABM identified that the ability of astrocytes to acquire, accumulate, and pass on mutations was enhanced during an activated state due to elevated levels of stress and proliferation caused by inflammation-induced injury. The proliferative capacity of astrocytes was increased by longer telomere length as a larger number of cell divisions were permitted before cell senescence. Simulations of 80-year trials suggest that this mechanism is plausible in explaining the role of longer telomere length in gliomagenesis.
Conclusion: Gliomagenesis is comprised of an intricate network of pathways that are the subject of ongoing research. The ABM effectively represents fundamental responses of neural tissue to inflammation-induced injury and indicates a plausible explanation for the role of longer telomere length in glioma oncogenesis. ABMs provide a means of defining a basic biological framework into which detailed elements can be dynamically incorporated in order to visualize, evaluate, and reshape hypotheses.