Effect of disrupted SOX18 transcription factor function on tumor growth, vascularization, and endothelial development

Simple item page
dc.contributor.authorYoung, N.
dc.contributor.authorHahn, C.
dc.contributor.authorPoh, A.
dc.contributor.authorDong, C.
dc.contributor.authorWilhelm, D.
dc.contributor.authorOlsson, J.
dc.contributor.authorMuscat, G.
dc.contributor.authorParsons, P.
dc.contributor.authorGamble, J.
dc.contributor.authorKoopman, P.
dc.date.issued2006
dc.description.abstractBackground: 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-7Ra = 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.
dc.description.statementofresponsibilityNeville Young, Christopher N. Hahn, Alisa Poh, Carolyn Dong, Dagmar Wilhelm, Jane Olsson, George E. O. Muscat, Peter Parsons, Jennifer R. Gamble and Peter Koopman
dc.identifier.citationJournal of the National Cancer Institute, 2006; 98(15):1060-1067
dc.identifier.doi10.1093/jnci/djj299
dc.identifier.issn0027-8874
dc.identifier.issn1460-2105
dc.identifier.orcidHahn, C. [0000-0001-5105-2554]
dc.identifier.urihttp://hdl.handle.net/2440/23423
dc.language.isoen
dc.publisherOxford Univ Press Inc
dc.rights© The Author 2006.
dc.source.urihttps://doi.org/10.1093/jnci/djj299
dc.subjectEndothelium, Vascular
dc.subjectUmbilical Veins
dc.subjectAnimals
dc.subjectMice, Inbred C57BL
dc.subjectHumans
dc.subjectMice
dc.subjectAdenoviridae
dc.subjectMelanoma
dc.subjectBreast Neoplasms
dc.subjectColorectal Neoplasms
dc.subjectNeovascularization, Pathologic
dc.subjectProteoglycans
dc.subjectHigh Mobility Group Proteins
dc.subjectTranscription Factors
dc.subjectAntigens
dc.subjectTransplantation, Homologous
dc.subjectBlotting, Northern
dc.subjectImmunohistochemistry
dc.subjectIn Situ Hybridization
dc.subjectCell Proliferation
dc.subjectCell Movement
dc.subjectGene Expression Regulation, Neoplastic
dc.subjectUp-Regulation
dc.subjectMutation
dc.subjectEmbryo, Mammalian
dc.subjectSOXF Transcription Factors
dc.subjectPlatelet Endothelial Cell Adhesion Molecule-1
dc.titleEffect of disrupted SOX18 transcription factor function on tumor growth, vascularization, and endothelial development
dc.typeJournal article
pubs.publication-statusPublished

Files

Collections

Medicine publications