Deregulation of tumor angiogenesis and blockade of tumor growth in PPARβ-deficient mice

Sabine Müller-Brüsselbach, Martin Kömhoff, Markus Rieck, Wolfgang Meissner, Kerstin Kaddatz, Jürgen Adamkiewicz, Boris Keil, Klaus J. Klose, Roland Moll, Andrew D. Burdick, Jeffrey M. Peters, Rolf Müller

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76 Scopus citations

Abstract

The peroxisome proliferator-activated receptor-β (PPARβ) 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 p57Kip2 as a PPARβ target gene and a mediator of the PPARβ-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 PPARβ in constraining tumor endothelial cell proliferation to allow for the formation of functional tumor microvessels.

Original languageEnglish (US)
Pages (from-to)3686-3698
Number of pages13
JournalEMBO Journal
Volume26
Issue number15
DOIs
StatePublished - Aug 8 2007

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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    Müller-Brüsselbach, S., Kömhoff, M., Rieck, M., Meissner, W., Kaddatz, K., Adamkiewicz, J., Keil, B., Klose, K. J., Moll, R., Burdick, A. D., Peters, J. M., & Müller, R. (2007). Deregulation of tumor angiogenesis and blockade of tumor growth in PPARβ-deficient mice. EMBO Journal, 26(15), 3686-3698. https://doi.org/10.1038/sj.emboj.7601803