PPARα deficiency in inflammatory cells suppresses tumor growth

PLoS ONE. 2007 Feb 28;2:e260

Speaker: 林怡璇                          Date: 2007/05/16 15:10~16:00

Commentator: 葉宣亨 博士                Place: Room 601

Abstract:

Inflammation has many roles in tumor growth and inhibition. Increased innate immune cells infiltrating to the tumor, such as macrophages, mast cells, and neutrophils, lead to increased angiogenesis and poor prognosis. Inversely, lymphocytic or monocytic inflammatory infiltrates can sometimes inhibit tumor growth and have more favorable prognosis^[1]. Peroxisome proliferator- activated receptor(PPAR)α, a ligand-activated nuclear receptor and transcription factor, mainly in modulating fatty acid transport and catabolism by regulating associated genes in earliest found, is a negative regulator of inflammation. Previous study showed that PPARα inhibits inflammation by ligand stimulation, whereas inflammation is enhanced in PPARα knock-out (KO) mice ^[2]. Recently, some investigators found that PPARα is necessary and sufficient fortumorgenesis^[3]. In this paper, the authors found that tumor growth and metastasis were inhibited in PPARα KO mice. In the in vivo vascular endothelial growth factor (VEGF) assay, fibroblast growth factor 2 (FGF2)-induced corneal neovascularization and VEGF-induced vascular permeability were inhibited in PPARα KO mice. Furthermore, overt inflammation in the absence of PPARα in the host tissue prevented tumor growth through excess production of the endogenous angiogenesis inhibitor thrombospondin-1 (TSP-1). Neutralization of TSP-1 by anti-TSP-1 antibody could restore tumor growth in PPARα KO mice. They further used bone marrow transplantation and granulocyte depletion to identify the role played by PPARα- expressing granulocytes in tumor growth. In this study, the authors add a new element to the emerging paradigm that tumor formation is not only a cell-autonomous process. Consequently, the action of genes involved in tumor formation must be seen in the broader context of host and tumor.

References:

1.          de Visser KE, et al. (2006) Paradoxical roles of the immune system during cancer development. Nat Rev Cancer 6: 24-37.

2.          Staels B, et al. (1998) Activation of human aortic smooth-muscle cells is inhibited by PPARalpha but not by PPARgamma activators. Nature 393: 790-793.

3.          Gonzalez FJ (2002) The peroxisome proliferator-activated receptor alpha (PPARα): role in hapatocarcinogenesis. Mol Cell Endocrinol 193: 71-79.