title: PPARalpha agonist fenofibrate suppresses tumor growth through direct and indirect angiogenesis inhibition.
abstract: Angiogenesis and inflammation are central processes through which the tumor microenvironment influences tumor growth. We have demonstrated recently that peroxisome proliferator-activated receptor (PPAR)alpha deficiency in the host leads to overt inflammation that suppresses angiogenesis via excess production of thrombospondin (TSP)-1 and prevents tumor growth. Hence, we speculated that pharmacologic activation of PPARalpha would promote tumor growth. Surprisingly, the PPARalpha agonist fenofibrate potently suppressed primary tumor growth in mice. This effect was not mediated by cancer-cell-autonomous antiproliferative mechanisms but by the inhibition of angiogenesis and inflammation in the host tissue. Although PPARalpha-deficient tumors were still susceptible to fenofibrate, absence of PPARalpha in the host animal abrogated the potent antitumor effect of fenofibrate. In addition, fenofibrate suppressed endothelial cell proliferation and VEGF production, increased TSP-1 and endostatin, and inhibited corneal neovascularization. Thus, both genetic abrogation of PPARalpha as well as its activation by ligands cause tumor suppression via overlapping antiangiogenic pathways. These findings reveal the potential utility of the well tolerated PPARalpha agonists beyond their use as lipid-lowering drugs in anticancer therapy. Our results provide a mechanistic rationale for evaluating the clinical benefits of PPARalpha agonists in cancer treatment, alone and in combination with other therapies.
authors.affiliation: Vascular Biology Program, Children's Hospital, Department of Surgery, Harvard Medical School, Boston, MA 02115, USA. dipak.panigrahy@childrens.harvard.edu
authors.forename: Dipak
authors.initials: D
authors.lastname: Panigrahy
authors.forename: Arja
authors.initials: A
authors.lastname: Kaipainen
authors.forename: Sui
authors.initials: S
authors.lastname: Huang
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Butterfield
authors.forename: Carmen M
authors.initials: CM
authors.lastname: Barnés
authors.forename: Michael
authors.initials: M
authors.lastname: Fannon
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Laforme
authors.forename: Deviney M
authors.initials: DM
authors.lastname: Chaponis
authors.forename: Judah
authors.initials: J
authors.lastname: Folkman
authors.forename: Mark W
authors.initials: MW
authors.lastname: Kieran
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003315:Cornea / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism; D004727:Endothelium / Q000378:metabolism; D011345:Fenofibrate / Q000494:pharmacology* / Q000627:therapeutic use; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009369:Neoplasms / Q000098:blood supply* / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D047493:PPAR alpha / Q000819:agonists* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism
chemical_list: D008024:Ligands; D047493:PPAR alpha; D016222:Fibroblast Growth Factor 2; D011345:Fenofibrate