Molecular Pathways: Dietary Regulation of Stemness and Tumor Initiation by the PPAR-δ Pathway

Abstract

Peroxisome Proliferator-Activated Receptor delta (PPAR-δ) is a nuclear receptor transcription factor that regulates gene expression during development and disease states such as cancer. However, the precise role of PPAR-δ during tumorigenesis is not well understood. Recent data suggest that PPAR-δ may have context specific oncogenic and tumor suppressive roles depending on the tissue, cell-type, or diet-induced physiology in question. For example in the intestine, pro-obesity diets, like a high fat diet (HFD), are associated with increased colorectal cancer incidence. Interestingly, many of the effects of a HFD in the stem and progenitor cell compartment are driven by a robust PPAR-δ program and contribute to the early steps of intestinal tumorigenesis. Importantly, the PPAR-δ pathway or its downstream mediators may serve as therapeutic intervention points or biomarkers in colon cancer that particularly arise in obese patients. Although potent PPAR-δ agonists and antagonists exist, their clinical utility may be enhanced by uncovering how PPAR-δ mediates tumorigenesis in diverse tissues and cell-types as well as in response to diet.

Peroxisome Proliferator-Activated Receptor Modulation during Metabolic Diseases and Cancers: Master and Minions

“…In addition, PPAR δ is required for chronic colonic inflammation and colitis-associated carcinogenesis: specifically, the cyclooxygenase (COX)-2-derived prostaglandin E2 (PGE2) signalling mediates crosstalk between tumor epithelial cells and macrophages to promote chronic inflammation and colitis-associated tumor genesis [78]. In agreement with what reported in the previous chapters, high-fat diet is associated with increased colorectal cancer incidence, probably because many of its effects on stem and progenitor cell compartment are driven by a robust PPAR- δ program and contribute to the early steps of intestinal tumorigenesis [79]. In addition, recent evidence suggests that high-fat diet modifies the PPAR γ pathway leading to disruption of microbial and physiological ecosystem in murine small intestine [80].…”

The PPAR–microbiota–metabolic organ trilogy to fine‐tune physiology

“…To date, there is no PPAR-b/d-specific agonist approved by the FDA on the market. The use of PPAR-b/d agonists in human clinical trials has been dampened after a preclinical mouse model showing protumorigenic effects, although antitumorigenic properties of PPAR-b/d have also been reported (95,(103)(104)(105). Just recently, Seladelpar (MBX-8025; CymaBay Therapeutics, Newark, CA, USA), a novel and potent PPAR-b/d selective agonist, has been approved for a long-term clinical trial for treating conditions such as primary biliary cirrhosis and NASH (95,106).…”

A high-fat diet induces a microbiota-dependent increase in stem cell activity in the Drosophila intestine

“…In mammals, HFDs directly enhance activity of ISCs, leading to increased villi lengths in the small intestine; a reaction that involves ß-catenin signaling [8]. This HFD induced activation appears to be directly caused by the lipid content of the food [3,9]. A recent study could show that confrontation with high lipid contents induces a very robust PPAR-δ activation in ISCs, thus enhancing the numbers of mitotically active cells in the intestine [9] [10].…”