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Integrin ß3 Overexpression Suppresses Tumor Growth in a Human Model of Gliomagenesis

Implications for the Role of ß3 Overexpression in Glioblastoma Multiforme

Department of Neurological Surgery and The Brain Tumor Research Center, University of California-San Francisco, San Francisco, California

Vß3 integrin complexes are overexpressed in the growing, invading margins of human glioblastoma multiforme (GBM) and in the GBM vasculature, suggesting a key role for Vß3 in GBM growth and invasion. The function of Vß3 complexes in tumor formation, however, has been challenged by studies showing that loss of Vß3 expression (via loss of ß3) in the host vasculature enhances, rather than suppresses, the growth of s.c. implanted carcinomas. To directly address the role of tumor-specific Vß3 overexpression in glioma formation, we increased Vß3 expression (via overexpression of a wild-type or constitutively activated ß3) in human astrocytes genetically modified to form anaplastic astrocytoma-like tumors (Ras cells) on intracranial injection in rats. Overexpression of ß3 selectively increased levels of Vß3 integrin complexes, but had no effect on anchorage-dependent or -independent growth in vitro. After intracranial injection, however, the Ras + ß3 cells formed fewer and smaller tumors than did Ras cells. Similarly, Ras-transformed mouse astrocytes that were derived from control animals formed smaller intracranial tumors than those derived from ß3 knockout animals. Although tumors formed by human Ras and Ras + ß3 cells were similar in blood vessel density, Ras + ß3 tumors had smaller, pericyte-depleted vessels and were significantly more hypoxic, suggesting a ß3-mediated vascular defect. The growth-suppressive actions of ß3, however, could be overcome by stimulation of pathways (Akt or vascular endothelial growth factor) commonly activated in GBM. These results show that tumor-specific Vß3 overexpression has growth-suppressive effects in gliomas, but that these deleterious effects are mitigated by alterations common to Vß3-overexpressing GBM.

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