Abstract 5: Experimentally-driven mathematical model of tumor angiogenesis mediated by multiple angiogenic factors
Authors: Li Ding , Hixon Danielle D. , Mumenthaler Shannon M. , Finley Stacey D. 
Published: July 2021

Abstract
Tumor angiogenesis is regulated by multiple pro- and anti-angiogenic factors. Anti-angiogenic drugs target the interconnected network of these angiogenic factors to inhibit neovascularization and tumor growth. However, current anti-angiogenic therapeutics targeting a single angiogenic factor show limited clinical success, prompting the development of combination anti-angiogenic therapy targeting multiple angiogenic factors simultaneously. In cases where anti-angiogenic therapy may be effective, tumors display a wide range of responses, which is not fully understood.
In this work, we use an integrative in vitro imaging and mathematical modeling approach to investigate how tumor angiogenesis is systematically regulated by multiple angiogenic factors and to study the effects of anti-angiogenic therapy. We particularly focus on two pro-angiogenic factors, vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (FGF2), and two anti-angiogenic factors, thrombospondin-1 (TSP1) and platelet factor 4 (PF4). In our in vitro experimental setting human endothelial cells are cultured in a microfluidic organ-on-chip chip platform exposed to angiogenic factors or in the presence of cancer cells to mimic the tumor microenvironment. The cellular responses induced by various concentrations of angiogenic factors are measured through a high content screening (HCS) confocal imaging system to quantify the cell counts, morphological features and vessel characteristics. These data are used to construct a novel mathematical model to capture how the angiogenic factors mediate cross-talk between tumor cells and endothelial cells. By fitting the model to the experimental measurements, we are able to predict the temporal dynamics of cell numbers and concentrations of the angiogenic factors.
Using the model, we generate insights into the effects of angiogenic factors and various anti-angiogenic treatments on tumor cells and endothelial cells. Excitingly, the model can also be applied to investigate how the effect of anti-angiogenic therapy is influenced by inter-tumor heterogeneity. For example, we identified that tumors with lower tumor cell growth rate and higher carrying capacity have a stronger response to anti-VEGF treatment, which indicates that variation in tumor cell growth rates can be a main reason for the observed heterogenous response to anti-VEGF therapy. In addition, we investigate a novel hypothesis regarding synergy between anti-angiogenic and chemotherapeutic agents with the model. Our simulated results suggest a new mechanism in which the chemotherapeutic agent enhances anti-angiogenic therapy simply through reducing the tumor cell growth rate.
Overall, this work generates novel insights into the function of multiple angiogenic factors in tumor angiogenesis, providing a tool that can be further used to test and optimize anticancer therapy.
Citation Format: Ding Li, Danielle D. Hixon, Shannon M. Mumenthaler, Stacey D. Finley. Experimentally-driven mathematical model of tumor angiogenesis mediated by multiple angiogenic factors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 5.