Receptor cross-talk in angiogenesis: Mapping environmental cues to cell phenotype using a stochastic, Boolean signaling network model

Abstract Cancer invasion and metastasis depend on tumor-induced angiogenesis, the means by which cancer cells attract and maintain a blood supply. During angiogenesis, cellular processes are tightly coordinated by signaling molecules and their receptors. Understanding how endothelial cells synthesize multiple biochemical signals can catalyze the development of novel therapeutic strategies to combat cancer. This study is the first to propose a signal transduction model highlighting the cross-talk between key receptors involved in angiogenesis, namely the VEGF, integrin, and cadherin receptors. From experimental data, we construct a network model of receptor cross-talk and analyze its dynamics. We identify relationships between receptor activation combinations and cellular function, and show that cross-talk is crucial to phenotype determination. The network converges to a unique set of output states that correspond to known cell phenotypes: migratory, proliferating, quiescent, apoptotic, and it predicts one phenotype that challenges the “go or grow” hypothesis. Finally, we use the model to study protein inhibition and to suggest molecular targets for anti-angiogenic therapies.