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Integrin beta3 overexpression suppresses tumor growth in a human model of gliomagenesis: implications for the role of beta3 overexpression in glioblastoma multiforme.

Abstract：

:alphaVbeta3 integrin complexes are overexpressed in the growing, invading margins of human glioblastoma multiforme (GBM) and in the GBM vasculature, suggesting a key role for alphaVbeta3 in GBM growth and invasion. The function of alphaVbeta3 complexes in tumor formation, however, has been challenged by studies showing that loss of alphaVbeta3 expression (via loss of beta3) in the host vasculature enhances, rather than suppresses, the growth of s.c. implanted carcinomas. To directly address the role of tumor-specific alphaVbeta3 overexpression in glioma formation, we increased alphaVbeta3 expression (via overexpression of a wild-type or constitutively activated beta3) in human astrocytes genetically modified to form anaplastic astrocytoma-like tumors (Ras cells) on intracranial injection in rats. Overexpression of beta3 selectively increased levels of alphaVbeta3 integrin complexes, but had no effect on anchorage-dependent or -independent growth in vitro. After intracranial injection, however, the Ras + beta3 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 beta3 knockout animals. Although tumors formed by human Ras and Ras + beta3 cells were similar in blood vessel density, Ras + beta3 tumors had smaller, pericyte-depleted vessels and were significantly more hypoxic, suggesting a beta3-mediated vascular defect. The growth-suppressive actions of beta3, however, could be overcome by stimulation of pathways (Akt or vascular endothelial growth factor) commonly activated in GBM. These results show that tumor-specific alphaVbeta3 overexpression has growth-suppressive effects in gliomas, but that these deleterious effects are mitigated by alterations common to alphaVbeta3-overexpressing GBM.

journal_name

Cancer Res

journal_title

Cancer research

authors

Kanamori M,Vanden Berg SR,Bergers G,Berger MS,Pieper RO

doi

10.1158/0008-5472.can-03-3354

subject

Has Abstract

pub_date

2004-04-15 00:00:00

pages

2751-8

issue

eissn

0008-5472

issn

1538-7445

journal_volume

pub_type

杂志文章

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Integrin beta3 overexpression suppresses tumor growth in a human model of gliomagenesis: implications for the role of beta3 overexpression in glioblastoma multiforme.