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.
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 humanbreast 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 humancancers.
Authors: Margaret J Wat; Tyler F Beck; Andrés Hernández-García; Zhiyin Yu; Danielle Veenma; Monica Garcia; Ashley M Holder; Jeanette J Wat; Yuqing Chen; Carrie A Mohila; Kevin P Lally; Mary Dickinson; Dick Tibboel; Annelies de Klein; Brendan Lee; Daryl A Scott Journal: Hum Mol Genet Date: 2012-06-20 Impact factor: 6.150
Authors: Ganesh V Samant; Marcus O Schupp; Mathias François; Silvia Moleri; Rajendra K Kothinti; Chang Zoon Chun; Indranil Sinha; Suzanna Sellars; Noah Leigh; Kallal Pramanik; Mark A Horswill; Indulekha Remadevi; Keguo Li; George A Wilkinson; Niloofar M Tabatabai; Monica Beltrame; Peter Koopman; Ramani Ramchandran Journal: J Biol Chem Date: 2011-07-05 Impact factor: 5.157
Authors: Moira K O'Bryan; Shuji Takada; Claire L Kennedy; Greg Scott; Shun-ichi Harada; Manas K Ray; Qunsheng Dai; Dagmar Wilhelm; David M de Kretser; E Mitch Eddy; Peter Koopman; Yuji Mishina Journal: Dev Biol Date: 2008-02-13 Impact factor: 3.582