The Emerging Role of Peroxisome Proliferator-Activated Receptors in Cancer Stemness

The peroxisome proliferator-activated receptors (PPAR-α, PPAR-δ, and PPAR-γ) are transcription factors that belong to the nuclear hormone receptor superfamily. Upon activation by specific lipids, they regulate gene expression by directly binding to PPAR response elements (PPREs) in the DNA. Although the functions of the different PPARs are specific to the isoform, tissue, and context, all three PPARs are generally involved in energy homeostasis through lipid sensing in physiological conditions. Importantly, there is increasing evidence linking PPARs with malignant behavior in cancer, regulating features frequently attributed to the aggressive subpopulation of cancer stem cells (CSCs): self-renewal, tumor initiation, chemoresistance, metastasis, and immune evasion. However, contradictory effects have been described for each isoform in various cancer types, and their implication in these malignant features may not consistently follow a pro- or anti-tumoral pattern. In this review, we revise the current knowledge on the role of the PPAR family members in cancer, with a special focus on cancer stemness, and discuss the potential for PPARs as therapeutic targets in CSC-driven relapse and resistance.