Deregulation of tumor angiogenesis and blockade of tumor growth in PPARbeta-deficient mice.
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.
Müller-Brüsselbach
Sabine
S
Institute of Molecular Biology and Tumor Research (IMT), Philipps-University, Marburg, Germany.
Kömhoff
Martin
M
Rieck
Markus
M
Meissner
Wolfgang
W
Kaddatz
Kerstin
K
Adamkiewicz
Jürgen
J
Keil
Boris
B
Klose
Klaus J
KJ
Moll
Roland
R
Burdick
Andrew D
AD
Peters
Jeffrey M
JM
Müller
Rolf
R
D000818:Animals; D049109:Cell Proliferation; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000378:metabolism; D015536:Down-Regulation; D004730:Endothelium, Vascular / Q000473:pathology; D008279:Magnetic Resonance Imaging; D051379:Mice; D018345:Mice, Knockout; D009374:Neoplasms, Experimental / Q000098:blood supply* / Q000473:pathology; D009389:Neovascularization, Pathologic; D020411:Oligonucleotide Array Sequence Analysis; D048068:PPAR-beta / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
C493965:Cdkn1c protein, mouse; D050761:Cyclin-Dependent Kinase Inhibitor p57; D048068:PPAR-beta