Multiscale Models of VEGF-mediated Molecular Signaling Pathways in Intratumoral Angiogenesis.

Abstract

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. Therefore a better understanding of it's mechanisms is essential for the development of anti cancer therapies. The goals of this dissertation are threefold: (1) detailed modelling of growth factor- receptor interactions, at a molecular level, (2) application of this information to aid the development of a multiscale delay differential equation (DDE) model of tumor angiogenesis, relating processes occurring at a cellular and intracellular level with global population behavior dynamics, (3) development of a hybrid model of tumor vascularization based on the theory of reinforced random walks, incorporating cellular chemotactic response to activated cell-surface receptors, governed by a novel chemotactic function. Using the DDE model, the potential of anti-angiogenic therapy targeting either the potent chemotactic and mitogenic cytokine CXCL8 or the pro-survival protein Bcl-2 for endothelial cells is evaluated. Bcl-2 is found to be the more effective target. Consequently, the model is expanded to allow for the testing of the therapeutic potential of a small molecule inhibitor of Bcl-2. A sensitivity analysis is carried out on various design parameters to aid in drug development. These results provide insight into the functioning of molecular signaling pathways that govern tumor growth and vascular development. Finally, a hybrid model of tumor angiogenesis is proposed which is, to the best of our knowledge, the first of its kind to account for experimentally observed phenomena such as endothelial cell polarization and response to activated cell-surface receptors. This lays the perfect groundwork for the incorporation of further details at a molecular level, of subcellular signaling cascades in models of tumor vascularization, that are able to account for spatial inhomogeneity in intra-tumoral vascular networks. Continued quantitative modelling in this direction may have profound implications for the development of novel therapies directed against specific proteins and chemokines.