Panigrahy Dipak, Kaipainen Arja, Huang Sui, Butterfield Catherine E, Barnés Carmen M, Fannon Michael, Laforme Andrea M, Chaponis Deviney M, Folkman Judah, Kieran Mark W
Vascular Biology Program, Children's Hospital, Department of Surgery, Harvard Medical School, Boston, MA 02115, USA.
Proc Natl Acad Sci U S A. 2008 Jan 22;105(3):985-90. doi: 10.1073/pnas.0711281105. Epub 2008 Jan 16.
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.
血管生成和炎症是肿瘤微环境影响肿瘤生长的核心过程。我们最近证明，宿主中过氧化物酶体增殖物激活受体（PPAR）α的缺乏会导致明显的炎症，通过血栓调节蛋白（TSP）-1的过量产生抑制血管生成，并阻止肿瘤生长。因此，我们推测PPARα的药物激活会促进肿瘤生长。令人惊讶的是，PPARα激动剂非诺贝特能有效抑制小鼠原发性肿瘤的生长。这种作用不是由癌细胞自主的抗增殖机制介导的，而是通过抑制宿主组织中的血管生成和炎症来实现的。虽然PPARα缺陷型肿瘤仍然对非诺贝特敏感，但宿主动物中PPARα的缺失消除了非诺贝特强大的抗肿瘤作用。此外，非诺贝特抑制内皮细胞增殖和VEGF产生，增加TSP-1和内皮抑素，并抑制角膜新生血管形成。因此，PPARα的基因敲除及其被配体激活均通过重叠的抗血管生成途径导致肿瘤抑制。这些发现揭示了耐受性良好的PPARα激动剂在抗癌治疗中除了用作降脂药物之外的潜在用途。我们的结果为评估PPARα激动剂在癌症治疗中单独使用以及与其他疗法联合使用的临床益处提供了机制依据。
