title: Effect of disrupted SOX18 transcription factor function on tumor growth, vascularization, and endothelial development.
abstract: BACKGROUND
  The growth of solid tumors depends on establishing blood supply; thus, inhibiting tumor angiogenesis has been a long-term goal in cancer therapy. The SOX18 transcription factor is a key regulator of murine and human blood vessel formation.
  
  
  METHODS
  We established allograft melanoma tumors in wild-type mice, Sox18-null mice, and mice expressing a dominant-negative form of Sox18 (Sox18RaOp) (n = 4 per group) and measured tumor growth and microvessel density by immunohistochemical analysis with antibodies to the endothelial marker CD31 and the pericyte marker NG2. We also assessed the affects of disrupted SOX18 function on MCF-7 human breast cancer and human umbilical vein endothelial cell (HUVEC) proliferation by measuring BrdU incorporation and by MTS assay, cell migration using Boyden chamber assay, and capillary tube formation in vitro. All statistical tests were two-sided.
  
  
  RESULTS
  Allograft tumors in Sox18-null and Sox18RaOp mice grew more slowly than those in wild-type mice (tumor volume at day 14, Sox18 null, mean = 486 mm3, 95% confidence interval [CI] = 345 mm3 to 627 mm3, P = .004; Sox18RaOp, mean = 233 mm3, 95% CI = 73 mm3 to 119 mm3, P<.001; versus wild-type, mean = 817 mm3, 95% CI = 643 mm3 to 1001 mm3) and had fewer CD31- and NG2-expressing vessels. Expression of dominant-negative Sox18 reduced the proliferation of MCF-7 cells (BrdU incorporation: MCF-7(Ra) = 20%, 95% CI = 15% to 25% versus MCF-7 = 41%, 95% CI = 35% to 45%; P = .013) and HUVECs (optical density at 490 nm, empty vector, mean = 0.46 versus SOX18 mean = 0.29; difference = 0.17, 95% CI = 0.14 to 0.19; P = .001) compared with control subjects. Overexpression of wild-type SOX18 promoted capillary tube formation of HUVECs in vitro, whereas expression of dominant-negative SOX18 impaired tube formation of HUVECs and the migration of MCF-7 cells via the disruption of the actin cytoskeleton.
  
  
  CONCLUSIONS
  SOX18 is a potential target for antiangiogenic therapy of human cancers.
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
authors.forename: Neville
authors.initials: N
authors.lastname: Young
authors.forename: Christopher N
authors.initials: CN
authors.lastname: Hahn
authors.forename: Alisa
authors.initials: A
authors.lastname: Poh
authors.forename: Carolyn
authors.initials: C
authors.lastname: Dong
authors.forename: Dagmar
authors.initials: D
authors.lastname: Wilhelm
authors.forename: Jane
authors.initials: J
authors.lastname: Olsson
authors.forename: George E O
authors.initials: GE
authors.lastname: Muscat
authors.forename: Peter
authors.initials: P
authors.lastname: Parsons
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Gamble
authors.forename: Peter
authors.initials: P
authors.lastname: Koopman
mesh_terms: D000256:Adenoviridae; D000818:Animals; D000941:Antigens / Q000032:analysis; D015152:Blotting, Northern; D001943:Breast Neoplasms / Q000098:blood supply / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000378:metabolism; D004622:Embryo, Mammalian / Q000378:metabolism; D004730:Endothelium, Vascular / Q000254:growth & development* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006609:High Mobility Group Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008545:Melanoma / Q000098:blood supply / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D009389:Neovascularization, Pathologic / Q000378:metabolism; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000032:analysis; D011509:Proteoglycans / Q000032:analysis; D055760:SOXF Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014184:Transplantation, Homologous; D014471:Umbilical Veins; D015854:Up-Regulation; D000099216:Chondroitin Sulfate Proteoglycan 4
chemical_list: D000941:Antigens; D006609:High Mobility Group Proteins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011509:Proteoglycans; D055760:SOXF Transcription Factors; D014157:Transcription Factors; D000099216:Chondroitin Sulfate Proteoglycan 4; C095473:SOX18 protein, human; C490653:Sox18 protein, mouse