title: CXCL12-CXCR7 axis is important for tumor endothelial cell angiogenic property.
abstract: We reported that tumor endothelial cells (TECs) differ from normal endothelial cells (NECs) in many aspects, such as gene expression profiles. Although CXCR7 is reportedly highly expressed in blood vessels of several tumors, its function in TECs is still unknown. To investigate this role, we isolated TECs from mouse tumor A375SM xenografts, and compared them with NECs from normal mouse dermis. After confirming CXCR7 upregulation in TECs, we analyzed its function using CXCR7 siRNA and CXCR7 inhibitor; CCX771. CXCR7 siRNA and CCX771 inhibited migration, tube formation and resistance to serum starvation in TECs but not in NECs. ERK1/2 phosphorylation was inhibited by CXCR7 knockdown in TECs. These results suggest that CXCR7 promotes angiogenesis in TECs via ERK1/2 phosphorylation. Using ELISA, we also detected CXCL12, a ligand of CXCR7, in conditioned medium from TECs, but not from NECs. CXCL12 neutralizing antibody significantly inhibited TEC random motility. VEGF stimulation upregulated CXCR7 expression in NECs, implying that VEGF mediates CXCR7 expression in endothelial cells. A CXCR7 inhibitor, CCX771 also inhibited tumor growth, lung metastasis and tumor angiogenesis in vivo. Taken together, the CXCL12-CXCR7 autocrine loop affects TEC proangiogenic properties, and could be the basis for an antiangiogenic therapy that specifically targets tumor blood vessels rather than normal vessels.
authors.affiliation: Department of Vascular Biology, Frontier Research Unit, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.|Department of Vascular Biology, Hokkaido University Graduate School of Dental Medicine, Sapporo, Japan.|Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Yamada
authors.affiliation: Department of Vascular Biology, Frontier Research Unit, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.|Department of Vascular Biology, Hokkaido University Graduate School of Dental Medicine, Sapporo, Japan.
authors.forename: Nako
authors.initials: N
authors.lastname: Maishi
authors.affiliation: Department of Vascular Biology, Frontier Research Unit, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.|Department of Vascular Biology, Hokkaido University Graduate School of Dental Medicine, Sapporo, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Akiyama
authors.affiliation: Department of Vascular Biology, Frontier Research Unit, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.|Department of Vascular Biology, Hokkaido University Graduate School of Dental Medicine, Sapporo, Japan.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Towfik Alam
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 Vascular Biology, Hokkaido University Graduate School of Dental Medicine, Sapporo, Japan.
authors.forename: Taisuke
authors.initials: T
authors.lastname: Kawamoto
authors.affiliation: 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 Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Norihiko
authors.initials: N
authors.lastname: Takahashi
authors.affiliation: Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Toshiya
authors.initials: T
authors.lastname: Kamiyama
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 Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Akinobu
authors.initials: A
authors.lastname: Taketomi
authors.affiliation: Department of Vascular Biology, Frontier Research Unit, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.|Department of Vascular Biology, Hokkaido University Graduate School of Dental Medicine, Sapporo, Japan.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Hida
mesh_terms: D000818:Animals; D019898:Autocrine Communication; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism*; D042783:Endothelial Cells / Q000502:physiology; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000098:blood supply / Q000378:metabolism* / Q000556:secondary; D020935:MAP Kinase Signaling System; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D054387:Receptors, CXCR / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology
chemical_list: C501896:ACKR3 protein, human; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D054387:Receptors, CXCR; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A
keywords: CXCR7; angiogenesis; tumor endothelial cells