c-Myc is essential for vasculogenesis and angiogenesis during development and tumor progression
- Troy A. Baudino1,
- Catriona McKay1,
- Helene Pendeville-Samain1,
- Jonas A. Nilsson1,
- Kirsteen H. Maclean1,
- Elsie L. White1,
- Ann C. Davis3,
- James N. Ihle1,2,4, and
- John L. Cleveland1,4,5
- 1Department of Biochemistry and 2Howard Hughes Medical Institute, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA; 3Pharmaceutical Division, Bayer Corporation, West Haven, Connecticut 06516, USA; 4Department of Molecular Sciences, University of Tennessee, Memphis, Tennessee 38163, USA
Abstract
c-Myc promotes cell growth and transformation by ill-defined mechanisms. c-myc −/− mice die by embryonic day 10.5 (E10.5) with defects in growth and in cardiac and neural development. Here we report that the lethality of c-myc −/−embryos is also associated with profound defects in vasculogenesis and primitive erythropoiesis. Furthermore, c-myc −/−embryonic stem (ES) and yolk sac cells are compromised in their differentiative and growth potential. These defects are intrinsic to c-Myc, and are in part associated with a requirement for c-Myc for the expression of vascular endothelial growth factor (VEGF), as VEGF can partially rescue these defects. However, c-Myc is also required for the proper expression of other angiogenic factors in ES and yolk sac cells, including angiopoietin-2, and the angiogenic inhibitors thrombospondin-1 and angiopoietin-1. Finally, c-myc −/− ES cells are dramatically impaired in their ability to form tumors in immune-compromised mice, and the small tumors that sometimes develop are poorly vascularized. Therefore, c-Myc function is also necessary for the angiogenic switch that is indispensable for the progression and metastasis of tumors. These findings support the model wherein c-Myc promotes cell growth and transformation, as well as vascular and hematopoietic development, by functioning as a master regulator of angiogenic factors.
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Footnotes
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↵5 Corresponding author.
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E-MAIL john.cleveland{at}stjude.org; FAX (901) 525-8025.
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Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/gad.1024602.
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- Received July 18, 2002.
- Accepted August 6, 2002.
- Cold Spring Harbor Laboratory Press