Agent-Based Simulations of In Vitro Multicellular Tumor Spheroid Growth

Multicellular tumor spheroids (MTS) are an in vitro model system of avascular tumors. They are used to study how local microenvironments affect cellular growth, viability, and therapeutic response. We are developing in silico, agent-based analogues to provide new options for gaining exploitable insight into both the in vitro and in vivo systems. MTS exhibit characteristic phenotypic attributes: initial exponential growth becomes linear and is followed by growth saturation and a stabilization of spheroid size; and a concentric layered structure, consisting of an outer shell of proliferating cells, an intermediate layer of viable but quiescent cells, and an inner necrotic core. Our agent-based, discrete event analogue consists of different spaces for tumor cells, oxygen, nutrient, and toxic inhibitors. It successfully simulates the three phases of spheroid growth and achieves the balance of cell gain and loss that is necessary for saturation. When exposed to varying levels of nutrient and oxygen, the model behavior is qualitatively similar to that observed in vitro. A goal is to have increasing overlap between the phenotype of the analogue in silico systems and the phenotype of their in vitro referents. The development process will necessarily expose gaps in the understanding of tumor spheroids and lead experimentalists in new and novel directions.