Glioblastoma multiforme is one of the deadliest cancers, in part because tumor cells rapidly migrate to the surrounding brain tissue, thereby making the tumor difficult to treat. Microglia are immune cells that, in their normal phenotype M1, kill intracellular micro-organisms and tumor cells. However, tumor cells can secrete chemokines such as CSF-1 that induce a transition of microglia to an activated M2 phenotype that secrete factors that in turn stimulate growth and invasiveness of tumor cells. In effect, tumor cells subvert the normal immune response and promote further tumor growth and dispersal through a molecular feedback process. For example, experimentalists have shown that the growth factor TGF-beta produced by M2 microglia is crucial for promotion of tumor invasion. In this study we seek to understand the interactions between the tumor cells and the microglia that enhance tumor growth, and for this purpose we develop a mathematical and computational model that involves reaction-diffusion equations for the important components in the interaction. These include the densities of tumor and microglial cells, and the concentrations of growth factors and other signaling molecules. We apply this model to a transwell assay used in the laboratory to demonstrate that microglia can stimulate tumor cell invasion by secreting Tgf-beta. We show that the model can both replicate the major components of the experimental findings and make new predictions to guide future experiments aimed at the development of new therapeutic approaches. Sensitivity analysis is used to identify the most important parameters as an aid to future experimental work. Despite incomplete information on the details of the M1 M2 transition in gliomas, the model consistently predicts the role of microglia in promoting glioma invasion in vitro. Thus, computational studies may provide insights to guide experiments aimed at the development of new therapeutic approaches.
Keywords: Hybrid model, Glioblastoma, microenvironment, microglia, TGFbeta, EGF, CSF-1 http://www-users.math.umn.edu/~othmer/