PPARs and tumor microenvironment: The emerging roles of the metabolic master regulators in tumor stromal-epithelial crosstalk and carcinogenesis

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.