Journal
EMBO JOURNAL
Volume 26, Issue 15, Pages 3686-3698Publisher
WILEY
DOI: 10.1038/sj.emboj.7601803
Keywords
hyperplasia; peroxisome proliferator-activated receptor beta/delta; p57(KIP2)/Cdkn1c; tumor angiogenesis; tumor growth
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Funding
- NCI NIH HHS [R01 CA124533, CA97999, R01 CA097999, R01 CA089607, CA89607, CA124533] Funding Source: Medline
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The peroxisome proliferator-activated receptor-beta (PPAR beta) has been implicated in tumorigenesis, but its precise role remains unclear. Here, we show that the growth of syngeneic Pparb wild-type tumors is impaired in Pparb(-/-) mice, concomitant with a diminished blood flow and an abundance of hyperplastic microvascular structures. Matrigel plugs containing pro-angiogenic growth factors harbor increased numbers of morphologically immature, proliferating endothelial cells in Pparb(-/-) mice, and retroviral transduction of Pparb triggers microvessel maturation. We have identified the Cdkn1c gene encoding the cell cycle inhibitor p57(Kip2) as a PPARb target gene and a mediator of the PPAR beta-mediated inhibition of cell proliferation, which provides a possible mechanistic explanation for the observed tumor endothelial hyperplasia and deregulation of tumor angiogenesis in Pparb(-/-) mice. Our data point to an unexpected essential role for PPARb in constraining tumor endothelial cell proliferation to allow for the formation of functional tumor microvessels.
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