| Autor: |
Young, Neville, Hahn, Christopher N., Poh, Alisa, Dong, Carolyn, Wilhelm, Dagmar, Olsson, Jane, Muscat, George E. O., Parsons, Peter, Gamble, Jennifer R., Koopman, Peter |
| Předmět: |
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| Zdroj: |
JNCI: Journal of the National Cancer Institute; 8/2/2006, Vol. 98 Issue 15, p1060-1067, 8p, 2 Color Photographs, 1 Black and White Photograph, 7 Graphs |
| Abstrakt: |
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-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. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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