Anti-angiogenic and anti-tumor activities of PPARα ligands
Authors: Dipak Panigrahy, Arja Kaipainen, Catherine E. Butterfield, Michael Fannon, Andrea M. Laforme, Marsha A. Moses, Gwen Louis, Judah Folkman, Mark W. Kieran
Journal: Cancer Research (2004)

Proc Amer Assoc Cancer Res, Volume 45, 2004

4784 

Peroxisome proliferator-activated receptor α (PPARα) is a ligand-activated nuclear receptor that is critical in inflammation and lipid metabolism. It is the molecular target of the fibrate class of lipid-lowering drugs, such as fenofibrate, which are orally administered, FDA-approved drugs widely used for the treatment of hyperlipidemia with minimal side effects. In animal models, PPARα ligands have been reported to inhibit tumor growth, although the mechanism of action remains unclear. We hypothesized the following: 1) tumor endothelium is a potential target of PPARα ligands; 2) PPARα ligands inhibit both endothelial (angiogenesis) and tumor cell growth, and the observed anti-tumor effect results from a synergism of both activities. To test this hypothesis, we first analyzed the expression pattern of PPARα in the endothelium of various tumors by immunofluorescent double-staining for PPARα and the endothelium marker CD31. PPARα was expressed in tumor cells and the endothelium of all tumors studied, as well as in 19 tumor cell lines. To demonstrate the effects of endothelial PPARα activation on cell proliferation, we analyzed five different PPARα ligands at doses that specifically activate PPARα. The PPARα ligand, fenofibrate, exhibited the most inhibition of bFGF and VEGF-induced proliferation of endothelial cells. Moreover, fenofibrate inhibited VEGF-stimulated endothelial cell migration and capillary tube formation. In addition to these direct anti-angiogenic effects in vitro, PPARα ligands also had effects on tumor cells that suggest indirect anti-angiogenic activity. Fenofibrate suppressed bFGF and VEGF production and increased thrombospondin-1 (TSP-1) levels in tumor cells. Fenofibrate also directly inhibited the proliferation of tumor cells. To study tumor cell invasion, we determined the effect of PPARα ligand treatment on MMP and TIMP activity; TIMP activity was increased in endothelial cells treated with PPARα ligands, while MMP levels were unaffected by the same treatment. In our in vivo studies, PPARα ligands suppressed angiogenesis by inhibiting corneal neovascularization induced by bFGF pellets. This effect was only observed in PPARα wildtype and not in PPARα null mice, demonstrating that the anti-angiogenic activity is mediated through PPARα. In addition, PPARα ligands inhibited VEGF-induced vascular permeability in vivo. Systemic oral administration with PPARα ligands inhibited primary tumor growth including experimental glioblastoma (U87) and fibrosarcoma (HT1080). Analysis of PPARα ligand-treated tumors revealed anti-angiogenic (decreased endothelial cell proliferation and increase in TSP-1), anti-inflammatory (decrease in leukocyte extravasation), and direct anti-tumor effects (decrease in tumor cell proliferation). Together, these results suggest that PPARα ligands may be useful in treating cancer by anti-tumor and anti-angiogenic effects.