title: Identification of tumor endothelial cells with high aldehyde dehydrogenase activity and a highly angiogenic phenotype.
abstract: Tumor blood vessels play an important role in tumor progression and metastasis. It has been reported that tumor endothelial cells (TECs) exhibit highly angiogenic phenotypes compared with those of normal endothelial cells (NECs). TECs show higher proliferative and migratory abilities than those NECs, together with upregulation of vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2). Furthermore, compared with NECs, stem cell markers such as Sca-1, CD90, and multidrug resistance 1 are upregulated in TECs, suggesting that stem-like cells exist in tumor blood vessels. In this study, to reveal the biological role of stem-like TECs, we analyzed expression of the stem cell marker aldehyde dehydrogenase (ALDH) in TECs and characterized ALDHhigh TECs. TECs and NECs were isolated from melanoma-xenografted nude mice and normal dermis, respectively. ALDH mRNA expression and activity were higher in TECs than those in NECs. Next, ALDHhigh/low TECs were isolated by fluorescence-activated cell sorting to compare their characteristics. Compared with ALDHlow TECs, ALDHhigh TECs formed more tubes on Matrigel-coated plates and sustained the tubular networks longer. Furthermore, VEGFR2 expression was higher in ALDHhigh TECs than that in ALDHlow TECs. In addition, ALDH was expressed in the tumor blood vessels of in vivo mouse models of melanoma and oral carcinoma, but not in normal blood vessels. These findings indicate that ALDHhigh TECs exhibit an angiogenic phenotype. Stem-like TECs may have an essential role in tumor angiogenesis.
authors.affiliation: Department of Vascular Biology, Hokkaido University Graduate School of Dental Medicine, Sapporo, Japan; Department of Orthodontics, Hokkaido University Graduate School of Dental Medicine, Sapporo, Japan.
authors.forename: Hitomi
authors.initials: H
authors.lastname: Ohmura-Kakutani
authors.affiliation: Department of Vascular Biology, Hokkaido University Graduate School of Dental Medicine, Sapporo, Japan; Division of Vascular Biology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Akiyama
authors.affiliation: Department of Vascular Biology, Hokkaido University Graduate School of Dental Medicine, Sapporo, Japan; Division of Vascular Biology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Nako
authors.initials: N
authors.lastname: Maishi
authors.affiliation: Department of Vascular Biology, Hokkaido University Graduate School of Dental Medicine, Sapporo, Japan.
authors.forename: Noritaka
authors.initials: N
authors.lastname: Ohga
authors.affiliation: Department of Cardiovascular and Thoracic Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Hida
authors.affiliation: Department of Vascular Biology, Hokkaido University Graduate School of Dental Medicine, Sapporo, Japan.
authors.forename: Taisuke
authors.initials: T
authors.lastname: Kawamoto
authors.affiliation: Department of Orthodontics, Hokkaido University Graduate School of Dental Medicine, Sapporo, Japan.
authors.forename: Junichiro
authors.initials: J
authors.lastname: Iida
authors.affiliation: Department of Oral Pathology and Biology, Hokkaido University Graduate School of Dental Medicine, Sapporo, Japan.
authors.forename: Masanobu
authors.initials: M
authors.lastname: Shindoh
authors.affiliation: Department of Renal and Genitourinary Surgery, Graduate School of Medicine, Sapporo, Japan.
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Tsuchiya
authors.affiliation: Department of Renal and Genitourinary Surgery, Graduate School of Medicine, Sapporo, Japan.
authors.forename: Nobuo
authors.initials: N
authors.lastname: Shinohara
authors.affiliation: Department of Vascular Biology, Hokkaido University Graduate School of Dental Medicine, Sapporo, Japan; Division of Vascular Biology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Hida
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D042783:Endothelial Cells / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008545:Melanoma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis / Q000235:genetics; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000032:analysis / Q000235:genetics
chemical_list: D042461:Vascular Endothelial Growth Factor A; D000444:Aldehyde Dehydrogenase; D040301:Vascular Endothelial Growth Factor Receptor-2