Deregulation of tumor angiogenesis and blockade of tumor growth in PPARbeta-deficient mice |
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Authors: | Müller-Brüsselbach Sabine Kömhoff Martin Rieck Markus Meissner Wolfgang Kaddatz Kerstin Adamkiewicz Jürgen Keil Boris Klose Klaus J Moll Roland Burdick Andrew D Peters Jeffrey M Müller Rolf |
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Affiliation: | Institute of Molecular Biology and Tumor Research (IMT), Philipps-University, Marburg, Germany. |
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Abstract: | The peroxisome proliferator-activated receptor-beta (PPARbeta) 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 PPARbeta target gene and a mediator of the PPARbeta-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 PPARbeta in constraining tumor endothelial cell proliferation to allow for the formation of functional tumor microvessels. |
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