Linking endothelial cell stimulation to tumor growth and vascular density: The VEGF - Bcl-2 - CXCL8 pathway

Tumor-induced angiogenesis is a highly complex process involving several cellular and subcellular events, and is critically dependent upon the activities of endothelial cells and the chemokines that stimulate them. A deeper understanding of the mechanisms that underlie the processes associated with angiogenesis is essential for the development of new anticancer therapies targeted against blood vessel development. In this chapter, we build a multiscale, delay differential equation model of tumor angiogenesis that begins by considering the effect of intracellular signal cascades on individual cell behavior, and we subsequently couple the impact of the biochemical microenvironment with these cellular processes. The model is then scaled up to a macroscopic view of global population dynamics as influenced by these intracellular pathways. In particular, we focus on the recently discovered VEGF-Bcl-2-CXCL8 pathway, associated with tumor cell-induced endothelial cell activation. We demonstrate the translational value of such modeling by applying our model to test the antiangiogenic potential of novel therapies targeting this pathway, including predictions of optimal drug design strategies.