Abstract
The nuclear receptor peroxisome proliferator-activated receptor β/δ (PPARβ/δ) is a lipid ligand-inducible transcription factor associated with macrophage polarization. However, its function in tumor-associated macrophages (TAMs) has not been investigated to date. Here, we report the PPARβ/δ-regulated transcriptome and cistrome for TAMs from ovarian carcinoma patients. Comparison with monocyte-derived macrophages shows that the vast majority of direct PPARβ/δ target genes are upregulated in TAMs and largely refractory to synthetic agonists, but repressible by inverse agonists. Besides genes with metabolic functions, these include cell type-selective genes associated with immune regulation and tumor progression, e.g., LRP5, CD300A, MAP3K8 and ANGPTL4. This deregulation is not due to increased expression of PPARβ/δ or its enhanced recruitment to target genes. Instead, lipidomic analysis of malignancy-associated ascites revealed high concentrations of polyunsaturated fatty acids, in particular linoleic acid, acting as potent PPARβ/δ agonists in macrophages. These fatty acid ligands accumulate in lipid droplets in TAMs, thereby providing a reservoir of PPARβ/δ ligands. These observations suggest that the deregulation of PPARβ/δ target genes by ligands of the tumor microenvironment contributes to the pro-tumorigenic polarization of ovarian carcinoma TAMs. This conclusion is supported by the association of high ANGPTL4 expression with a shorter relapse-free survival in serous ovarian carcinoma.
Highlights
Macrophages of the tumor microenvironment play a pivotal role in promoting the growth, invasion, metastazation and therapy resistance of malignant tumors, as suggested by the correlation of disease progression with macrophage density in different types of human cancer and shown in mouse tumor models [1, 2]
We have previously described that the synthetic peroxisome proliferator-activated receptor β/δ (PPARβ/δ) agonist L165,041 induces a morphology in monocyte-derived macrophage (MDM) that resembles that of IL-4 treated macrophages [28] (Figure 1B and 1C)
We found that PPARβ/δ target genes are inducible by ascites in murine bone marrow-derived macrophages (BMDMs), similar to human MDMs
Summary
Macrophages of the tumor microenvironment play a pivotal role in promoting the growth, invasion, metastazation and therapy resistance of malignant tumors, as suggested by the correlation of disease progression with macrophage density in different types of human cancer and shown in mouse tumor models [1, 2]. Under the influence of chemokines, cytokines and growth factors secreted by tumor cells and other host-derived cells, monocytes are recruited from the circulation and differentiate into tumorassociated macrophages (TAMs) that are programmed www.impactjournals.com/oncotarget to promote tumor progression [3,4,5]. Macrophages react to their microenvironment with an extreme plasticity [6], resulting in highly diverse phenotypes, with proinflammatory “M1” and anti-inflammatory “M2” macrophages [4] as the extremes. PPARβ/δ has been implicated in tumorigenesis in a number of studies with conflicting results [15], which may be due to divergent functions of the receptor in tumor cells and tumor-associated host cells as well as differences in the experimental models used (mouse strains, synthetic ligands)
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