A Multi-Scale Cell-Based Model to Simulate and Elucidate the Mechanisms Controlling Tumor-Induced Angiogenesis.

[摘要] Tumor-induced angiogenesis, which is the formation of new blood vessels from existing vasculature in response to chemical signals from a tumor, is a crucial step in cancer invasion and metastasis. Although the sequential steps involved in tumor-induced angiogenesis are well known, the interplay between the biochemical and biomechanical mechanisms (e.g., cell-cell and cell-ECM interactions, and intracellular signaling pathways) that affect angiogenesis is largely unresolved. The focus of this dissertation is to develop a multi-scale model of tumor-induced angiogenesis that considers the evolving composition of the stroma and the role of cellular interactions with its major component, the extracellular matrix, in order to better understand how to manipulate these processes for therapeutic gain. Key features of this biophysical model include: (1) linking processes occurring on multiple time scales, (2) controlling processes at the level of the individual cell, (3) using physical constraints and energy minimization to capture emergent behaviors without prescribing phenomenological rules, and (4) quantifying morphological details that are not currently possible to capture with continuous models. We develop a numerical code ANGIO implementing the biophysical model and simulate tumor-induced angiogenesis. Using ANGIO, we examine and report on the following critical scientific areas: (1) the relative importance of chemotaxis and mechanical forces in cell migration, (2) how the topology of the extracellular matrix influences cell migration and vascular structure, and (3) the relationship between external stimuli and cell phenotype. These results translate and synthesize a large body of compartmentalized research on angiogenesis and are meant to inform and advance efforts to develop new approaches for treating cancer and other angiogenesis-dependent diseases.

[发布机构] University of Michigan

[效力级别] Extracellular Matrix

[关键词] Multi-Scale Cell-Based Mathematical Model of Tumor-Induced Angiogenesis;Extracellular Matrix;Cellular Potts Model;Chemotaxis;Cell Motility;Signal Transduction Network;Mathematics;Science;Applied and Interdisciplinary Mathematics