Abstract
BackgroundThe epidermal growth factor receptor (EGFR) signaling pathway and angiogenesis in brain cancer act as an engine for tumor initiation, expansion and response to therapy. Since the existing literature does not have any models that investigate the impact of both angiogenesis and molecular signaling pathways on treatment, we propose a novel multi-scale, agent-based computational model that includes both angiogenesis and EGFR modules to study the response of brain cancer under tyrosine kinase inhibitors (TKIs) treatment.ResultsThe novel angiogenesis module integrated into the agent-based tumor model is based on a set of reaction–diffusion equations that describe the spatio-temporal evolution of the distributions of micro-environmental factors such as glucose, oxygen, TGFα, VEGF and fibronectin. These molecular species regulate tumor growth during angiogenesis. Each tumor cell is equipped with an EGFR signaling pathway linked to a cell-cycle pathway to determine its phenotype. EGFR TKIs are delivered through the blood vessels of tumor microvasculature and the response to treatment is studied.ConclusionsOur simulations demonstrated that entire tumor growth profile is a collective behaviour of cells regulated by the EGFR signaling pathway and the cell cycle. We also found that angiogenesis has a dual effect under TKI treatment: on one hand, through neo-vasculature TKIs are delivered to decrease tumor invasion; on the other hand, the neo-vasculature can transport glucose and oxygen to tumor cells to maintain their metabolism, which results in an increase of cell survival rate in the late simulation stages.
Highlights
The epidermal growth factor receptor (EGFR) signaling pathway and angiogenesis in brain cancer act as an engine for tumor initiation, expansion and response to therapy
We developed a multi-scale model by integrating a novel angiogenesis module into an agent-based tumor model based on a set of reaction–diffusion equations that describe the spatio-temporal evolution of the distributions of micro-environmental factors such as glucose, oxygen, TGFα, vascular endothelial growth factors (VEGF) and fibronectin
A system of ordinary differential equations simulates the dynamics of the EGFR signaling pathway and the cell cycle to determine the cells' phenotypic switch at the cellular scale
Summary
The epidermal growth factor receptor (EGFR) signaling pathway and angiogenesis in brain cancer act as an engine for tumor initiation, expansion and response to therapy. A hybrid discrete-continuum (HDC) model that couples a cellular automaton module with a continuum module was proposed by Anderson and co-workers [5,6] These models have not considered the effects of any gene-protein signaling pathways such as the EGFR pathway, computational cancer biologists have already studied them extensively. Tumor cells secret vascular endothelial growth factors (VEGF) [15,16] into the microenvironment to induce and sustain new capillary sprouts migrating from pre-existing vasculature towards the tumor. This in turn helps to maintain tumor cells’ metabolism by supplying them with glucose and oxygen and subsequently leads to metastasis. Our previous agent-based models [10,11,12,13,17] did not explicitly take tumor-induced angiogenesis into consideration
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