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.

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Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily that modu-

A role for the nuclear receptor peroxisome proliferator‐activated receptor‐β (PPARβ) in oncogenesis has been suggested by a number of observations but its precise role remains elusive. Prostaglandin I2 (PGI2, prostacyclin), a major arachidonic acid (AA) derived cyclooxygenase (Cox) product, has been proposed as a PPARβ agonist. Here, we show that the 4‐hydroxytamoxifen (4‐OHT) mediated activation of a C‐Raf‐estrogen receptor fusion protein leads to the induction of both the PPARβ and Cox‐2 genes, concomitant with a dramatic increase in PGI2 synthesis. Surprisingly, however, 4‐OHT failed to activate PPARβ transcriptional activity, indicating that PGI2 is insufficient for PPARβ activation. In agreement with this conclusion, the overexpression of ectopic Cox‐2 and PGI2 synthase (PGIS) resulted in massive PGI2 synthesis but did not activate the transcriptional activity of PPARβ. Conversely, inhibition of PGIS blocked PGI2 synthesis but did not affect the AA mediated activation of PPARβ. Our data obtained with four different cell types and different experimental strategies do not support the prevailing opinion that PGI2 plays a significant role in the regulation of PPARβ.

The peroxisome proliferator activated receptor-beta (PPARbeta) plays an essential role in lipid metabolism, immune modulation, differentiation and cell proliferation. There is also strong evidence for a function in oncogenesis and tumor vascularization, but the underlying molecular mechanisms remain elusive. In the present study, we have used fibroblasts derived from Pparb wild-type and null mice to determine by 2-DE and PMF analysis the contribution of PPARbeta to the protein profile of fibroblasts. Thirty-one differentially expressed proteins of different functional categories were identified. For at least two proteins a role in tumorigenesis and/or tumor vascularization has previously been reported: while the calcium intracellular channel-4 (CLIC4) was expressed at lower levels in Pparb null cells, expression of the cellular retinol binding protein 1 (CRBP1) was enhanced. Clic4 and Crbp1 gene expression patterns observed in different experimental settings in vitro and in vivo confirmed the proteomics data. Our findings indicate that the expression of a defined set of proteins is altered in fibroblasts and endothelial cells from Pparb null mice, that this is due to aberrant gene regulation, and that the altered expression of these proteins is consistent with the tumor vascularization phenotype of Pparb null mice.