A quantitative analysis of the development and remodeling of blood vessels in tumors : contribution of endothelial progenitor cells to angiogenesis and effect of solid stress on blood vessel morphology

Abstract

Angiogenesis plays a key role in tumor growth. The dependency of tumors on angiogenesis has rendered it a promising therapeutic target. However, to date, this promise has gone unfulfilled in the clinic, suggesting that the current understanding of angiogenesis is insufficient. The objective of this dissertation is to quantitatively analyze the effects of systemic biochemical and cellular contributions as well as local mechanical influences on angiogenesis using a combination of theoretical and experimental approaches. A model of the balance between angiogenic stimulators and inhibitors is developed to assess the effects of biochemical factors produced by the primary tumor on angiogenesis both locally and remotely. The model quantitatively describes how primary tumors can suppress metastases and provides a framework for assessing the conditions under which this may occur. The model also predicts a disruption of the balance between angiogenic and anti-angiogenic factors within the primary tumor that may result in distinct regions of angiogenesis stimulation and suppression, offering a new hypothesis for the experimentally observed formation of central necrosis. Based on these predictions of angiogenic activity within the primary tumor, a model of the contribution of endothelial progenitor cells to tumor angiogenesis is advanced. The model accurately captures the salient features of tumor growth and angiogenesis and predicts that endothelial progenitor cells make a significant contribution to tumor growth and angiogenesis. Model simulations of several anti-angiogenic therapeutic strategies indicate that effectively targeting pathways affecting both vessel wall-associated endothelial cells and circulating endothelial progenitor cells leads to improved outcome as compared to targeting either pathway alone.

(cont.) The hypothesis that unusual tumor blood vessel morphology is caused by solid mechanical interactions is investigated experimentally. Blood vessels in tumors receiving treatment cytotoxic to the tumor cells are significantly more open and circular than those in tumors receiving no treatment. The interaction and coupling between these biochemical, cellular, and mechanical influences on tumor angiogenesis and their potential biological and clinical implications are discussed.