title: Hypoxia-induced reactive oxygen species cause chromosomal abnormalities in endothelial cells in the tumor microenvironment.
abstract: There is much evidence that hypoxia in the tumor microenvironment enhances tumor progression. In an earlier study, we reported abnormal phenotypes of tumor-associated endothelial cells such as those resistant to chemotherapy and chromosomal instability. Here we investigated the role of hypoxia in the acquisition of chromosomal abnormalities in endothelial cells. Tumor-associated endothelial cells isolated from human tumor xenografts showed chromosomal abnormalities, >30% of which were aneuploidy. Aneuploidy of the tumor-associated endothelial cells was also shown by simultaneous in-situ hybridization for chromosome 17 and by immunohistochemistry with anti-CD31 antibody for endothelial staining. The aneuploid cells were surrounded by a pimonidazole-positive area, indicating hypoxia. Human microvascular endothelial cells expressed hypoxia-inducible factor 1 and vascular endothelial growth factor A in response to either hypoxia or hypoxia-reoxygenation, and in these conditions, they acquired aneuploidy in 7 days. Induction of aneuploidy was inhibited by either inhibition of vascular endothelial growth factor signaling with vascular endothelial growth factor receptor 2 inhibitor or by inhibition of reactive oxygen species by N-acetyl-L-cysteine. These results indicate that hypoxia induces chromosomal abnormalities in endothelial cells through the induction of reactive oxygen species and excess signaling of vascular endothelial growth factor in the tumor microenvironment.
authors.affiliation: Department of Vascular Biology, Hokkaido University Graduate School of Dental Medicine, Sapporo, Japan.
authors.forename: Miyako
authors.initials: M
authors.lastname: Kondoh
authors.forename: Noritaka
authors.initials: N
authors.lastname: Ohga
authors.forename: Kosuke
authors.initials: K
authors.lastname: Akiyama
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Hida
authors.forename: Nako
authors.initials: N
authors.lastname: Maishi
authors.forename: Alam Mohammad
authors.initials: AM
authors.lastname: Towfik
authors.forename: Nobuo
authors.initials: N
authors.lastname: Inoue
authors.forename: Masanobu
authors.initials: M
authors.lastname: Shindoh
authors.forename: Kyoko
authors.initials: K
authors.lastname: Hida
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000235:genetics; D002869:Chromosome Aberrations; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics*; D042783:Endothelial Cells / Q000378:metabolism*; D006801:Humans; D000860:Hypoxia / Q000378:metabolism / Q000503:physiopathology*; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism; D059785:Karyotype; D051379:Mice; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment / Q000235:genetics*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D051793:Hypoxia-Inducible Factor 1; D017382:Reactive Oxygen Species; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2