Increased angiogenesis in Cdk4(R24C/R24C):Apc(+/Min) intestinal tumors.
Cyclin dependent kinase 4 (Cdk4) is a cell cycle regulator involved in early G1 cell cycle progression and has been indirectly implicated in angiogenesis in the Min mouse system, a mouse that harbors a mutation in the Apc gene. Apc(+/Min) mice when crossed with Ink4a/arf-/- mice, exhibited increased angiogenesis of colorectal tumors suggesting that dysregulation of Cdk4 (due to loss of Ink4a-mediated suppression) may contribute to enhanced angiogenesis. To demonstrate a direct role for Cdk4 in angiogenesis, we crossed mice that have an activated Cdk4, Cdk4(R24C/R24C) mice, with Apc(+/Min) mice and examined levels of angiogenesis in intestinal tumors formed. Our results show an increase in the percentage of highly vascularized tumors in Cdk4(R24C/R24C):Apc(Min/+) and Cdk4(+/R24C):Apc(Min/+) mice compared to Cdk4(+/+):Apc(Min/+) mice. In addition immunohistochemical analysis showed an increase in CD-31 staining localized to endothelial cells of Cdk4(R24C/R24C):Apc(Min/+) mouse tumors, supporting the hypothesis of increased vasculature in these tumors. Further analysis showed an increase in the expression of the E2F1 target proteins Vegf-b and Cyclin A in Cdk4(R24C/R24C):Apc(+/Min) intestinal tumors. Together these data suggest that the dysregulated Cdk4 gene plays an important role in angiogenesis during intestinal tumor formation and may in part act via increasing E2F1 target proteins. This is the first report to show that Cdk4 has a direct role in angiogenesis in vivo and may be an important drug target to reduce or prevent angiogenesis during intestinal tumor formation.
Abedin
Zahidur R
ZR
Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, PA, USA.
Ma
Zhongjie
Z
Reddy
E Premkumar
EP
D000818:Animals; D002453:Cell Cycle; D019925:Cyclin A / Q000096:biosynthesis; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics / Q000378:metabolism*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000172:deficiency / Q000235:genetics; D050687:E2F1 Transcription Factor / Q000096:biosynthesis; D042783:Endothelial Cells / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D017491:Genes, APC; D007414:Intestinal Neoplasms / Q000098:blood supply* / Q000235:genetics / Q000378:metabolism*; D007422:Intestines / Q000098:blood supply; D051379:Mice; D009154:Mutation; D009389:Neovascularization, Pathologic; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D042561:Vascular Endothelial Growth Factor B / Q000096:biosynthesis / Q000235:genetics
D019925:Cyclin A; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050687:E2F1 Transcription Factor; C493754:E2f1 protein, mouse; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D042561:Vascular Endothelial Growth Factor B; C495902:Cdk4 protein, mouse; D051358:Cyclin-Dependent Kinase 4