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ID4 promotes the growth of glioblastoma multiforme by mediating MGP-enhanced angiogenesis.

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Call No.	RC280.B7 K89 2008
Author	Kuzontkoski, Paula M.
Title	ID4 promotes the growth of glioblastoma multiforme by mediating MGP-enhanced angiogenesis.
Date	2008
Abstract	ID proteins are naturally occurring dominant negative HLH-transcription factors that are highly expressed during development but generally not expressed in adult tissue except for selected cell types and some stem cells. Also, aberrant expression occurs in a number of cancers. We observed that ID4 was elevated in glioblastoma multiforme (GBM) and GBM-derived cell lines. To assess if ID4 provides a growth advantage to GBM we injected GBM-derived cultures, engineered to express ID4 at elevated levels, into immunosuppressed mice. Cultures with elevated ID4 levels yielded much larger xenografts than cultures with endogenous ID4 levels; however, their in vitro proliferative and apoptotic rates were nearly identical. Increased vascular density in the tumors with elevated ID4 suggested that ID4 may be enhancing angiogenesis. Array studies comparing the expression of genes in GBM-derived cultures with elevated ID4 and isogenic control cultures identified matrix GLA protein (MGP), a secreted 14.2 kD protein, as the potential mediator of this neovascularization. Media conditioned by GBM-derived cultures expressing elevated levels of ID4 enhanced endothelial cell proliferation and tube formation, a surrogate in vitro assay for angiogenesis and a known activity of MGP. To determine if MGP mediates the growth of GBM with elevated ID4, we engineered GBM-derived cultures with elevated ID4 and MGP, and cultures with elevated ID4 and levels of MGP diminished by an sh MGP expression plasmid. These were evaluated for tumor formation and growth in mice. The xenografts with diminished levels of MGP were smaller and less vascularized than the control xenografts with higher MGP levels. These data indicate that ID4 promotes the growth of GBM tumors, at least in part, by enhancing MGP-mediated angiogenesis. We suggest that ID4 and MGP may be potential biomarkers for the progression of GBM and that they should be considered further as potential targets for anti-angiogenic therapies in the treatment of GBM.
Description	x, 103 leaves : ill. 28 cm.
Format	application/pdf
Advisor	Mark A. Israel
Subject	Glioblastoma multiforme. DNA-binding proteins. Transcription factors. Extracellular matrix proteins. Neovascularization.
College	Dartmouth Medical School -- Department of Genetics.
Issuing Body	Dartmouth Dissertations are made available through the Dartmouth Digital Library.
Degree	Thesis (Ph.D.)--Dartmouth College.
Copyright	All rights reserved. No part of this book may be reproduced in any form by any electronic or mechanical means without permission in writing from the author.
DOI	http://dx.doi.org/10.1349/ddlp.182

Title	Page 1
Format	application/pdf
Issuing Body	Dartmouth Dissertations are made available through the Dartmouth Digital Library.
Degree	Thesis (Ph.D.)--Dartmouth College.
Full Text	ID4 PROMOTES THE GROWTH OF GLIOBLASTOMA MULTIFORME BY MEDIATING MGP-ENHANCED ANGIOGENESIS A Thesis Submitted to the Faculty in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Genetics by Paula M. Kuzontkoski DARTMOUTH COLLEGE Hanover, New Hampshire May 2008 Examining Committee: _____________________________ Mark A. Israel, MD _____________________________ Yashi F. Ahmed, MD, PhD _____________________________ James D. Gorham, MD, PhD _____________________________ Carol J. Thiele, PhD _____________________________ Charles K. Barlowe, PhD Dean of Graduate Studies

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