Abstract

Simple SummaryThe roles of peroxisome proliferator-activated receptors (PPARs) in carcinogenesis are increasingly appreciated. With the growing interest in tumor stromal-epithelial crosstalk, we aim to provide an up-to-date overview of the implications of PPARs in the tumor microenvironment. In the tumor stromal cells, the nuclear receptors exhibit critical, but functionally diverse activities, rendering it hard to ascribe either an exclusive pro- or anti-tumorigenic role for different PPAR isotypes. Based on the existing evidence, we also highlight the knowledge gaps and future prospects of targeting PPARs in the tumor microenvironment. Essentially, a PPAR-based anticancer approach holds a great deal of untapped potential, but its success relies on innovative strategies for cell-specific or tumor microenvironment-triggered drug delivery systems.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.

Highlights

  • The year 2020 marks the 30-year discovery of nuclear hormone receptor, peroxisome proliferator-activated receptors (PPARs)

  • A recent study revealed that PPARβ/δ upregulates Nanog expression in colorectal cancer cells, promoting metastasis when exposed to a fat-enriched environment [54]; yet, another study showed its suppressive effect on SOX2 expression, inhibiting neuroblastoma tumorigenesis [55]

  • As Peroxisome proliferator-activated receptors (PPARs) may have vastly distinct roles in tumor stromal cells compared to epithelial cells during tumorigenesis, we will provide an overview of the current understanding of PPARs in the TME and the interplay between tumor stroma and epithelium

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Summary

Introduction

The year 2020 marks the 30-year discovery of nuclear hormone receptor, peroxisome proliferator-activated receptors (PPARs). In the majority of cases, the activation of PPARβ/δ is linked to tumor progression, whereas PPARα and PPARγ are associated with anti-tumorigenesis [10]. Enhanced response of Erk to transforming growth factor β1 (TGF-β1) is seen in prostate cancer cells, in response to PPARβ/δ-mediated activation of ABCA1 and caveolin-1, which results in TGF-β1-induced tumor growth, migration, and invasion [53]. A recent study revealed that PPARβ/δ upregulates Nanog expression in colorectal cancer cells, promoting metastasis when exposed to a fat-enriched environment [54]; yet, another study showed its suppressive effect on SOX2 expression, inhibiting neuroblastoma tumorigenesis [55]. The conflicting results suggest other still hidden mechanisms that can fine-tune the cellular activity of PPARβ/δ towards pro- or anticancer effects

Clinical Development of PPAR Modulators as Cancer Therapeutics
The Roles of PPARs in Stromal Cells in the Tumor Microenvironment
Cancer-Associated Adipocytes
PPAR-Dependent Autocrine and Paracrine Signaling
Role of ANGPTL4 in Stromal–Epithelial Crosstalk
Stromal PPARγ Modulates Tumor Metastasis
Findings
Conclusions
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