{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T17:15:16Z","timestamp":1793121316487,"version":"4.5.0"},"reference-count":39,"publisher":"National Academy of Sciences","issue":"3","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2008,1,22]]},"abstract":"<jats:p>Angiogenesis and inflammation are central processes through which the tumor microenvironment influences tumor growth. We have demonstrated recently that peroxisome proliferator-activated receptor (PPAR)\u03b1 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 PPAR\u03b1 would promote tumor growth. Surprisingly, the PPAR\u03b1 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 PPAR\u03b1-deficient tumors were still susceptible to fenofibrate, absence of PPAR\u03b1 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 PPAR\u03b1 as well as its activation by ligands cause tumor suppression via overlapping antiangiogenic pathways. These findings reveal the potential utility of the well tolerated PPAR\u03b1 agonists beyond their use as lipid-lowering drugs in anticancer therapy. Our results provide a mechanistic rationale for evaluating the clinical benefits of PPAR\u03b1 agonists in cancer treatment, alone and in combination with other therapies.<\/jats:p>","DOI":"10.1073\/pnas.0711281105","type":"journal-article","created":{"date-parts":[[2008,1,16]],"date-time":"2008-01-16T20:53:53Z","timestamp":1200516833000},"page":"985-990","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":240,"title":["PPAR\u03b1 agonist fenofibrate suppresses tumor growth through direct and indirect angiogenesis inhibition"],"prefix":"10.1073","volume":"105","author":[{"given":"Dipak","family":"Panigrahy","sequence":"first","affiliation":[{"name":"*Vascular Biology Program, Children's Hospital, Department of Surgery, Harvard Medical School, Boston, MA 02115;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arja","family":"Kaipainen","sequence":"additional","affiliation":[{"name":"*Vascular Biology Program, Children's Hospital, Department of Surgery, Harvard Medical School, Boston, MA 02115;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sui","family":"Huang","sequence":"additional","affiliation":[{"name":"*Vascular Biology Program, Children's Hospital, Department of Surgery, Harvard Medical School, Boston, MA 02115;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine E.","family":"Butterfield","sequence":"additional","affiliation":[{"name":"*Vascular Biology Program, Children's Hospital, Department of Surgery, Harvard Medical School, Boston, MA 02115;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen M.","family":"Barn\u00e9s","sequence":"additional","affiliation":[{"name":"*Vascular Biology Program, Children's Hospital, Department of Surgery, Harvard Medical School, Boston, MA 02115;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Fannon","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY 40536"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea M.","family":"Laforme","sequence":"additional","affiliation":[{"name":"*Vascular Biology Program, Children's Hospital, Department of Surgery, Harvard Medical School, Boston, MA 02115;"},{"name":"Division of Pediatric Oncology, Dana\u2013Farber Cancer Institute, Harvard Medical School, Boston, MA 02115; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deviney M.","family":"Chaponis","sequence":"additional","affiliation":[{"name":"*Vascular Biology Program, Children's Hospital, Department of Surgery, Harvard Medical School, Boston, MA 02115;"},{"name":"Division of Pediatric Oncology, Dana\u2013Farber Cancer Institute, Harvard Medical School, Boston, MA 02115; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judah","family":"Folkman","sequence":"additional","affiliation":[{"name":"*Vascular Biology Program, Children's Hospital, Department of Surgery, Harvard Medical School, Boston, MA 02115;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark W.","family":"Kieran","sequence":"additional","affiliation":[{"name":"*Vascular Biology Program, Children's Hospital, Department of Surgery, Harvard Medical School, Boston, MA 02115;"},{"name":"Division of Pediatric Oncology, Dana\u2013Farber Cancer Institute, Harvard Medical School, Boston, MA 02115; and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2008,1,22]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI27989"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/384039a0"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/18.11.2029"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrc1254"},{"key":"e_1_3_4_5_2","first-page":"3241","article-title":"Peroxisome proliferator-activated receptor\u03b1 is an androgen-responsive gene in human prostate and is highly expressed in prostatic adenocarcinoma.","volume":"6","author":"Collett GP","year":"2000","unstructured":"GP Collett, et al., Peroxisome proliferator-activated receptor\u03b1 is an androgen-responsive gene in human prostate and is highly expressed in prostatic adenocarcinoma. Clin Cancer Res 6, 3241\u20133248 (2000).","journal-title":"Clin Cancer Res"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1002\/mc.10061"},{"key":"e_1_3_4_7_2","first-page":"2424","article-title":"Ligands for peroxisome proliferator-activated receptors\u03b1 and \u03b3 inhibit chemically induced colitis and formation of aberrant crypt foci in rats.","volume":"61","author":"Tanaka T","year":"2001","unstructured":"T Tanaka, et al., Ligands for peroxisome proliferator-activated receptors\u03b1 and \u03b3 inhibit chemically induced colitis and formation of aberrant crypt foci in rats. Cancer Res 61, 2424\u20132428 (2001).","journal-title":"Cancer Res"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.20519"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1186\/1476-4598-5-13"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1002\/1098-2744(200011)29:3<134::AID-MC2>3.0.CO;2-F"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00403-004-0479-y"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-05-2556"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-06-0722"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M701429200"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.99.24.3125"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.med.53.082901.104018"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-291X(02)00385-6"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-003-2322-6"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000113781.08139.81"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.atherosclerosis.2005.10.047"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9149(01)01486-2"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm990554g"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20050964"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0000260"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM197108122850711"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature01322"},{"key":"e_1_3_4_27_2","first-page":"6090","article-title":"Concomitant suppression of hyperlipidemia and intestinal polyp formation in Apc-deficient mice by peroxisome proliferator-activated receptor ligands.","volume":"63","author":"Niho N","year":"2003","unstructured":"N Niho, et al., Concomitant suppression of hyperlipidemia and intestinal polyp formation in Apc-deficient mice by peroxisome proliferator-activated receptor ligands. Cancer Res 63, 6090\u20136095 (2003).","journal-title":"Cancer Res"},{"key":"e_1_3_4_28_2","first-page":"825","article-title":"Therapeutic treatment of DMBA-induced mammary tumors with PPAR ligands.","volume":"21","author":"Pighetti GM","year":"2001","unstructured":"GM Pighetti, et al., Therapeutic treatment of DMBA-induced mammary tumors with PPAR ligands. Anticancer Res 21, 825\u2013829 (2001).","journal-title":"Anticancer Res"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI0215634"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.ATV.0000250972.83623.61"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2005.08.007"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(04)00102-9"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.99.13.1726"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI11497"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M206966200"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1097\/00045391-200305000-00007"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1067\/mjd.2002.124607"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.1097\/01.mph.0000183863.10792.d4"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrc1369"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.0711281105","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,12]],"date-time":"2022-04-12T16:52:16Z","timestamp":1649782336000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.0711281105"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2008,1,22]]},"references-count":39,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2008,1,22]]}},"alternative-id":["10.1073\/pnas.0711281105"],"URL":"https:\/\/doi.org\/10.1073\/pnas.0711281105","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2008,1,22]]},"assertion":[{"value":"2007-09-07","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2008-01-22","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}