title: 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.
authors.affiliation: Department of Neurological Surgery and The Brain Tumor Research Center, University of California-San Francisco, San Francisco, California, USA.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Kanamori
authors.forename: Scott R
authors.initials: SR
authors.lastname: Vanden Berg
authors.forename: Gabriele
authors.initials: G
authors.lastname: Bergers
authors.forename: Mitchel S
authors.initials: MS
authors.lastname: Berger
authors.forename: Russell O
authors.initials: RO
authors.lastname: Pieper
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D001932:Brain Neoplasms / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D002455:Cell Division / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000378:metabolism* / Q000473:pathology; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D005909:Glioblastoma / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000096:biosynthesis / Q000502:physiology; D039661:Integrin beta3 / Q000096:biosynthesis / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis
chemical_list: D039302:Integrin alphaVbeta3; D039661:Integrin beta3; D011518:Proto-Oncogene Proteins; D042461:Vascular Endothelial Growth Factor A; C494918:AKT1 protein, human; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt