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

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.

Department dc:contributor.department

Massachusetts Institute of Technology. Dept. of Chemical Engineering.

Grantor dc:publisher

Massachusetts Institute of Technology

Year dc:date.issued

2003

Author dc:creator

• Stoll, Brian R. (Brian Richard), 1973-

Advisor dc:contributor.advisor

• Robert S. Langer and Rakesh K. Jain.

• Chemical Engineering.

Statement dc:rights

• M.I.T. theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. See provided URL for inquiries about permission.

Licence dc:rights.uri

• http://dspace.mit.edu/handle/1721.1/7582

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/1721.1/29606

OAI identifier oai:identifier

oai:dspace.mit.edu:1721.1/29606