A new study from the researchers at the University of Michigan Rogel Cancer Center suggests that high-fat diets and those substances touted as athletic performance enhancers can activate receptors that accelerate precancerous lesions into becoming pancreatic cancer.

Most pancreatic cancers arise from pancreatic intraepithelial neoplasia, a precancerous lesion found among 55% to 80% of adults over 40 years old. The study shows that pre-cancerous lesions in mice contain higher levels of the transcriptional receptor peroxisome proliferation activated receptor-delta (PPARδ) linked to pancreatic cancer.

Pancreatic Cancer: High-Fat Diets, Unregulated Athletic Performance Enhancers Activate Receptor for Pre-Cancerous Lesions
(Photo : Unsplash/National Cancer Institute)
Pancreatic Desmoplasia

Peroxisome Proliferator Activated Receptor-Delta (PPARδ) Explained

According to the Principles of Bone Biology (3rd Edition) published in 2008, the nuclear receptor PPARδ is a transcription factor that serves as a metabolic sensor for endogenous ligands, like lipophilic hormones, dietary fatty acids, and some lipid metabolites. That means it is involved in regulating genes implicated in fatty acid oxidation, cholesterol metabolism, and thermogenesis.

Moreover, PPARδ plays an important role in energy metabolism, controlling fatty acids, glucose oxidation, redox homeostasis, mitochondrial biogenesis, cardiomyocyte proliferation, inflammation, and cancer formation.

Activation of this nuclear receptor accelerates the progression of precancerous pancreas lesions into becoming pancreatic cancer, Medical Xpress reported. Study author Dr. Imad Shureiqi said they became interested in the effects of PPARδ on pancreatic carcinogenesis after prior observations suggested it increased the risk for gastrointestinal cancers.

Activation of PPARδ is linked to excessive exposure to certain natural and synthetic ligands. Some natural ligands could be found in high-fat diets, associated with an increased risk for pancreatic cancer in humans and animals.

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Synthetic Ligands Found in Exercise Supplements

Aside from natural ligands, some synthetic forms of PPARδ ligands are also found in substances in exercise supplements that aim to boost athletic performance. An example of this is the Cardarine (GW501516), originally designed to encourage the body to use more fat and treat diabetes and hyperlipemia.

However, its production and other similarly potent PPARδ agonists for medical use have already been discontinued because of their potential precancerous side effects. However, there are still unregulated internet outlets that still sell these substances and market them to young people, claiming that they will help build muscle and burn fat.

Shureiqi explains in a news release via EurekAlert! that researchers initially found these synthetic forms of PPARδ ligands reduced fatigue in mice, which gained its nickname "exercise in a pill." Unfortunately, the media failed to address the substance's harmful side effects of helping cancer cells get energy from fats.

Animal models suggest a strong correlation between PPARδ and cancer promotion in the gastrointestinal tract, including colorectal and stomach cancer. Through this research, scientists gain more information and knowledge about how this nuclear receptor affects pancreatic cancer.

Critical factors that promote the progression of precancerous lesions to pancreatic cancer remain poorly understood. Although not all of them develop into cancer, understanding their progression is critical in finding interventions to address the rise of pancreatic cancer cases.

The study and other similar researches indicate that people with silent or low-grade precancerous lesions could increase their risk of having pancreatic cancer if they regularly consume natural and synthetic PPARδ activators.

The study results can be found in the paper titled "Rapid Acceleration of KRAS-Mutant Pancreatic Carcinogenesis via Remodeling of Tumor Immune Microenvironment by PPARδ," published in Nature Communications. 

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