Date of Award

2011

Degree Type

Dissertation

Department

Biological, Geological and Environmental Sciences

First Advisor

Silverstein, Roy

Subject Headings

Neovascularization inhibitors, Tumors -- Blood-vessels -- Growth, Thrombospondin-1, Glycoproteins

Abstract

Cancer is typically thought of as an uncommon disease, in which solid tumors require a blood supply in order to grow and metastasize. Interestingly, upon autopsy a large portion of elderly individuals display numerous non-vascularized lesions throughout their bodies. Thus, the angiogenic switch in the development of cancer presents an important therapeutic target. Previous work by our laboratory has established an interaction between CD36, Histidine Rich Glycoprotein (HRGP) and Thrombospondin 1 (TSP-1) in the modulation of angiogenesis. Briefly, endothelial cell receptor CD36 interaction with soluble or cell bound TSP-1 leads to the induction of an apoptotic signaling cascade in vascular endothelial cells resulting in decreased proliferation, migration and tube formation, thereby inhibiting angiogenesis. Presence of soluble HRGP leads to inhibition of the anti-angiogenic potential of the CD36-TSP-1 pathway through a decoy receptor function whereby TSP-1is bound and sequestered. Previous studies have focused on this pathway with regards to wound healing. However, pathologically relevant modulation of angiogenesis is also observed in tumors. In the current work we evaluate the role of the CD36-TSP-HRGP pathway in tumor growth and angiogenesis. Further, we examine a possible processing mechanism by which TSP function may be modulated by a matrix metalloprotease, ADAMTS1.Chapters two through five will outline the role of the TSP-CD36 axis in tumor biology, namely angiogenesis and growth. We will also address modulation of this pathway via HRGP. Further we will describe a matrix metalloprotease mechanism by which TSP function may be regulated

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