PPARs and Tumor Microenvironment: The Emerging Roles of the Metabolic Master Regulators in Tumor Stromal-Epithelial Crosstalk and Carcinogenesis

Abstract

Peroxisome proliferator-activated receptors (PPARs) have been extensively studied for more than three decades. Consisting of three isotypes, PPARα, γ, and β/δ, these nuclear receptors are regarded as the master metabolic regulators which govern many aspects of the body energy homeostasis and cell fate. Their roles in malignancy are also increasingly recognized. With the growing interest in crosstalk between tumor stroma and epithelium, this review aims to highlight the current knowledge on the implications of PPARs in the tumor microenvironment. PPARγ plays a crucial role in the metabolic reprogramming of cancer-associated fibroblasts and adipocytes, coercing the two stromal cells to become substrate donors for cancer growth. Fibroblast PPARβ/δ can modify the risk of tumor initiation and cancer susceptibility. In endothelial cells, PPARβ/δ and PPARα are pro- and anti-angiogenic, respectively. Although the angiogenic role of PPARγ remains ambiguous, it is a crucial regulator in autocrine and paracrine signaling of cancer-associated fibroblasts and tumor-associated macrophages/immune cells. Of note, angiopoietin-like 4 (ANGPTL4), a secretory protein encoded by a target gene of PPARs, triggers critical oncogenic processes such as inflammatory signaling, extracellular matrix derangement, anoikis resistance and metastasis, making it a potential drug target for cancer treatment. To conclude, PPARs in the tumor microenvironment exhibit oncogenic activities which are highly controversial and dependent on many factors such as stromal cell types, cancer types, and oncogenesis stages. Thus, the success of PPAR-based anticancer treatment potentially relies on innovative strategies to modulate PPAR activity in a cell type-specific manner.

Keywords: cancer-associated adipocyte; cancer-associated fibroblast; metabolic reprogramming; peroxisome proliferation-activated receptor; tumor-associated macrophage.

Figure 1

The cellular activities regulated by PPARs in tumor epithelium. In a tumor cell, PPARα and PPARγ exhibit controversial roles. They are generally linked to anticancer effects (green text boxes) by impairing the pro-inflammatory, pro-metastatic, and pro-survival responses, as well as reducing metabolic flexibility. However, their pro-cancer activities (red text boxes), including the maintenance of cancer stemness, meeting high energy demands of cancers and promoting metastasis, have been reported. On the other hand, PPARβ/δ activates signaling pathways and key mediators implicated in pro-cancer activities such as enhanced survival, proliferation, and epithelial–mesenchymal transition. ECM, extracellular matrix.

Figure 2

PPARγ orchestrates the metabolic reprogramming of cancer-associated fibroblasts and adipocytes. In cancer-associated fibroblasts (CAFs), PPARγ interacts closely with HIF-1α, AMPK, and NF-κB to promote cell cycle arrest, senescence, autophagy, and glycolysis. These functional changes unleash many metabolic substrates into the tumor microenvironment for the neighboring tumor cells. Similarly, PPARγ governs the fate and function of cancer-associated adipocytes (CAAs). Upon exposure to adipogenic stimuli, PPARγ mediates adipogenesis and formation of CAAs to act as an energy reserve. In contrast, exposure to dedifferentiation stimuli drives CAAs to adopt a CAF-like phenotype and act as a substrate doner in the tumor microenvironment. Certain miRNAs can suppress PPARγ to induce brown and beige differentiation of CAAs which are also energy donors for cancer progression.

Figure 3

Stromal PPARβ/δ regulates epithelial redox homeostasis and oncogenesis. In carcinogenic assaults, TGFβ signaling in epithelial cells is activated to promote H₂O₂ synthesis, which subsequently activates NRF2 and reinforces the cytoprotection against carcinogens (blue upper compartment of the epithelial cell). However, fibroblast PPARβ/δ disrupts the protective mechanism by upregulating LRG1, which acts as a competitive inhibitor of TGFβ1 and dampens TGFβ signaling, resulting in increased cancer susceptibility and oncogenesis (red lower compartment of the epithelial cell).

Figure 4

Angiogenic role of PPARs in endothelial cells. In the endothelial cells, PPARα exhibits an anti-angiogenic effect by inhibiting endothelial proliferation, whereas PPARβ/δ appears pro-angiogenic by ensuring proper endothelial morphogenesis and vascular maturation. The role of PPARγ in angiogenesis is conflicting and warrants further investigation.

Figure 5

PPARs modulate stromal–epithelial crosstalk in the tumor microenvironment. PPARs affect autocrine and paracrine signaling in different stromal cells. In cancer-associated fibroblasts, PPARγ activation upon ligand binding represses NF-κB, alleviating the secretion of many autocrine and paracrine signals. However, in macrophages and immune cells, PPARγ activation is primarily linked to pro-cancer activities, such as the formation of tumor-associated macrophages (TAMs), increased regulatory T cells, and immunotolerance. ANGPTL4 is a target gene product of PPARs. Proteolytic cleavage of full-length ANGPTL4 yields nANGPTL4 and cANGPTL4 domains, of which the latter is a potent paracrine signal and key mediator of inflammatory signals, anoikis resistance, and metastasis.

Figure 6

Possible strategies to target stromal PPARs for precision oncology. In this review, we propose four strategies to achieve PPAR-based precision oncology, including (i) cell-specific exosomes, (ii) TME-sensing nanoparticles, (iii) targeting pro-tumorigenic PPAR gene targets with immunotherapy, and (iv) stratification of PPAR-related TME molecular fingerprints. The features of each strategy are summarized in the figure.