The Emerging Role of PPAR Beta/Delta in Tumor Angiogenesis

Figure 1

The “hallmark” role of PPAR beta/delta in tumor angiogenesis and progression. (a) Interplay between PPAR beta/delta and downstream key signal molecules. In the signal network of proangiogenic molecules, COX2 promotes the secretion of VEGF and MMPs including MMP9; COX2 infiltration also mediates IL1 beta-induced angiogenesis, which further activates VEGF; COX2 also contributes to cancer progression through the enhancement of the angiogenic chemokine CXCL8 (IL8) expression. IL8 drives VEGF activation and induces MMP9 expression. LEPTIN induces MMP9 expression, enhances COX2 activity, or transactivates VEGFR to facilitate angiogenesis. WT1 transactivates ETS1, TRF2, and c-KIT. ETS1 further upregulates the MMP9, VEGF, and VEGFR expression. In turn, VEGF is also a major inducer of ETS1. TRF2 transactivates PDGFR beta, and c-KIT may affect angiogenesis through the promotion of VEGF production. There exists a crosstalk between VEGF and MMP9 and between VEGF, VEGFR, and PDGFB and PDGFR beta. Oval shape: they represent those molecules that have been identified as direct target genes of PPAR beta/delta; rectangle shape: they represent those molecules that are significantly upregulated upon PPAR beta/delta overexpression. (b) Function of PPAR beta/delta at diverse cellular levels in TME. In TME, multiple distinct cells communicate and collaborate to enable tumor growth and progression. These cells include cancer cells, CSCs, ECs, EPCs, PCs, SMCs, CAFs, and tumor-infiltrating inflammatory cells. PPAR beta/delta can directly function on ECs and EPCs, or directly take action on them by regulating downstream signal molecules such as VEGF, MMP9, PDGFB, PDGFR beta, and SOX18. PDGFB and PDGFR beta regulate vascular permeability and maturation through the recruitment of PCs and SMCs. c-KIT also functions on ECs, c-KIT, and NANOG and may regulate the stemness to control cancer progression. ETS1 regulates MMP9 expression in CAFs; the crosstalk between CAFs and PDGFR beta also exists. PPAR beta/delta may act on tumor-infiltrating myeloid cells through the modulation of the IL10, IL8, CCL2, and PDGFR beta expression. As mentioned above, PPAR beta/delta stimulates cancer cell invasion and facilitates tumor angiogenesis in an IL10-dependent manner in tumor-infiltrating myeloid cells. IL8 can directly regulate angiogenesis via the recruitment of neutrophils. CCL2 is also a major regulator of recruitment of the myeloid monocytic cells such as MDSCs, TAMs, and dendritic cells. Also, PDGFR beta in stromal fibroblasts may mediate PDGFB-induced TAM recruitment. Among these molecules, SOX18, IL10, CCL2, and ETS1 are overexpressed upon PPAR beta/delta activation, and the others have been reported as direct targets of PPAR beta/delta.

(a)

(b)