A hybrid model of tumor growth and angiogenesis: In silico experiments.

Abstract

Tumor associated angiogenesis is the development of new blood vessels in response to proteins secreted by tumor cells. These new blood vessels allow tumors to continue to grow beyond what the pre-existing vasculature could support. Here, we construct a mathematical model to simulate tumor angiogenesis by considering each endothelial cell as an agent, and allowing the vascular endothelial growth factor (VEGF) and nutrient fields to impact the dynamics and phenotypic transitions of each tumor and endothelial cell. The phenotypes of the endothelial cells (i.e., tip, stalk, and phalanx cells) are selected by the local VEGF field, and govern the migration and growth of vessel sprouts at the cellular level. Over time, these vessels grow and migrate to the tumor, forming anastomotic loops to supply nutrients, while interacting with the tumor through mechanical forces and the consumption of VEGF. The model is able to capture collapsing and breaking of vessels caused by tumor-endothelial cell interactions. This is accomplished through modeling the physical interaction between the vasculature and the tumor, resulting in vessel occlusion and tumor heterogeneity over time due to the stages of response in angiogenesis. Key parameters are identified through a sensitivity analysis based on the Sobol method, establishing which parameters should be the focus of subsequent experimental efforts. During the avascular phase (i.e., before angiogenesis is triggered), the nutrient consumption rate, followed by the rate of nutrient diffusion, yield the greatest influence on the number and distribution of tumor cells. Similarly, the consumption and diffusion of VEGF yield the greatest influence on the endothelial and tumor cell numbers during angiogenesis. In summary, we present a hybrid mathematical approach that characterizes vascular changes via an agent-based model, while treating nutrient and VEGF changes through a continuum model. The model describes the physical interaction between a tumor and the surrounding blood vessels, explicitly allowing the forces of the growing tumor to influence the nutrient delivery of the vasculature.