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J. Biol. Chem., Vol. 281, Issue 48, 37256-37264, December 1, 2006

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Intracranial Microenvironment Reveals Independent Opposing Functions of Host V3 Expression on Glioma Growth and Angiogenesis^*

From the Department of Neurological Surgery and the Brain Tumor Research Center, University of California, San Francisco, California 94115-0875

V3 integrins are overexpressed in the host-derived vasculature of glioblastoma multiform (GBM) and are believed to contribute to angiogenesis and tumor growth. To directly address the role of host V3 expression in GBM growth and behavior, we intracranially implanted integrin 3-expressing GBM cells into 3 wild type (WT) or 3 knock out (KO) mice and monitored angiogenesis and growth. GBM in 3 WT animals had a vessel density greater than that in 3 KO animals, consistent with a pro-angiogenic, pro-tumorigenic view of host integrin function. GBM in 3 WT animals, however, were no larger than those in 3 KO animals, because GBM in 3WT animals were infiltrated with a higher number of tumor necrosis factor -secreting, apoptosis-inducing macrophages than the tumors in the corresponding 3 KO animals. The tumor-suppressive effects of host 3 expression could be reversed by macrophage depletion or by transplantation of bone marrow from 3 KO animals into 3 WT animals, both of which significantly increased tumor growth independently of tumor vessel density. Taken together, these results show that host V3 integrin expression has opposing actions in the intracranial setting, enhancing tumor vascularization and growth while independently enhancing macrophage-mediated tumor elimination. Appropriate management of these functions could lead to enhanced efficacy of anti-integrin based therapies for glioma.

Received for publication, June 5, 2006 , and in revised form, September 29, 2006.

^* This work was supported by National Institutes of Health Grant CA 94989 (to R. P.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1.

¹ These authors contributed equally to this work.

² To whom correspondence should be addressed: UCSF Cancer Center, 2340 Sutter St., Rm. N219, San Francisco, CA 94115-0875.

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