title: SDF-1 and CXCR4 are up-regulated by VEGF and contribute to glioma cell invasion.
abstract: Glioma cells produce vascular endothelial growth factor (VEGF) to induce vascularization and thereby supply the malignant tissue with oxygen and nutrients. However, little is known about the direct effects of VEGF on tumor cells. In this study, we investigate the ability of VEGF to promote proliferation and invasion of human glioma cells (U251n). Since the chemokine and its receptor, SDF-1/CXCR4, promote glioma cell proliferation and are up-regulated in human glioblastomas, we also tested the effects of VEGF on SDF-1 and CXCR4 mRNA expression. Using cell culture, the effect of VEGF on proliferation of U251n cells was measured using ELISA to detect incorporated BrdU as a marker of DNA syntheses. The effects of VEGF and SDF-1 on U251n cell invasion and proliferation were measured using inhibitors to VEGF receptor1 and receptor2, DC101 and MF1, respectively, and a CXCR4 antagonist (AMD3100). SDF-1 and CXCR4 mRNA expression in U251n and U87MG cells were measured using quantitative PCR. VEGF antisense phosphorothioate oligodeoxynucleotide (AS-VEGF) was also used to down-regulate VEGF expression in U251n cells. VEGF significantly increased U251n cell proliferation and invasion in a dose-dependent manner. These effects were blocked by the VEGF receptor inhibitors, DC101/MF1. The CXCR4 antagonist AMD3100 blocked U251n increased invasion, but not proliferation. CXCR4 and SDF-1 mRNA were up-regulated when U251n and U87MG cells were treated with VEGF. Eight micrometer VEGF antisense phosphorothioate oligodeoxynucleotide (AS-VEGF) down-regulated CXCR4 and SDF-1 mRNA levels in U251n cells. VEGF has a direct effect on U251n glioma cell proliferation and invasion. VEGF up-regulates SDF-1 and CXCR4 mRNA expression, and contributes to U251n cell invasion.
authors.affiliation: Department of Neurosurgery, Henry Ford Heath Science Center, Detroit, MI 48202, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Hong
authors.forename: Feng
authors.initials: F
authors.lastname: Jiang
authors.forename: Steven N
authors.initials: SN
authors.lastname: Kalkanis
authors.forename: Zheng Gang
authors.initials: ZG
authors.lastname: Zhang
authors.forename: Xue-Peng
authors.initials: XP
authors.lastname: Zhang
authors.forename: Ana C
authors.initials: AC
authors.lastname: DeCarvalho
authors.forename: Mark
authors.initials: M
authors.lastname: Katakowski
authors.forename: Kevin
authors.initials: K
authors.lastname: Bobbitt
authors.forename: Tom
authors.initials: T
authors.lastname: Mikkelsen
authors.forename: Michael
authors.initials: M
authors.lastname: Chopp
mesh_terms: D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D002633:Chemotaxis / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D005910:Glioma; D006801:Humans; D009361:Neoplasm Invasiveness; D012333:RNA, Messenger / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000235:genetics / Q000494:pharmacology*
chemical_list: C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D012333:RNA, Messenger; D019718:Receptors, CXCR4; D011994:Recombinant Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A