View the Current Issue

Article

  • The EMBO Journal (2007) 26, 3686 - 3698
  • doi:10.1038/sj.emboj.7601803

Published online: 19 July 2007

Deregulation of tumor angiogenesis and blockade of tumor growth in PPARbold beta-deficient mice

Sabine Müller-Brüsselbach1,a, Martin Kömhoff2,a, Markus Rieck1,a, Wolfgang Meissner1, Kerstin Kaddatz1, Jürgen Adamkiewicz1, Boris Keil3, Klaus J Klose3, Roland Moll4, Andrew D Burdick5, Jeffrey M Peters5 and Rolf Müller1

  1. Institute of Molecular Biology and Tumor Research (IMT), Philipps-University, Marburg, Germany
  2. Department of Pediatrics, Philipps-University, Baldingerstrasse, Marburg, Germany
  3. Department of Diagnostic Radiology, Small Animal and Molecular Imaging Center, Philipps-University, Baldingerstrasse, Marburg, Germany
  4. Institute of Pathology, Philipps-University, Baldingerstrasse, Marburg, Germany
  5. Department of Veterinary and Biomedical Sciences and Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, PA, USA

Correspondence to:

Rolf Müller, Institute of Molecular Biology and Tumor Research (IMT), Philipps-University, Emil-Mannkopff-Strasse 2, Marburg 35032, Germany. Tel.: +49 6421 2866236; Fax: +49 6421 2868923; E-mail: rmueller@imt.uni-marburg.de

aThese authors contributed equally to this work

Received 25 January 2007; Accepted 29 June 2007

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 p57Kip2 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.

  • Keywords:

    • hyperplasia,
    • peroxisome proliferator-activated receptor beta/delta,
    • p57KIP2/Cdkn1c,
    • tumor angiogenesis,
    • tumor growth