ROS release by PPARβ/δ-null fibroblasts reduces tumor load through epithelial antioxidant response

Oncogene. 2018 Apr;37(15):2067-2078. doi: 10.1038/s41388-017-0109-8. Epub 2018 Jan 25.

Abstract

Tumor stroma has an active role in the initiation, growth, and propagation of many tumor types by secreting growth factors and modulating redox status of the microenvironment. Although PPARβ/δ in fibroblasts was shown to modulate oxidative stress in the wound microenvironment, there has been no evidence of a similar effect in the tumor stroma. Here, we present evidence of oxidative stress modulation by intestinal stromal PPARβ/δ, using a FSPCre-Pparb/d-/- mouse model and validated it with immortalized cell lines. The FSPCre-Pparb/d-/- mice developed fewer intestinal polyps and survived longer when compared with Pparb/dfl/fl mice. The pre-treatment of FSPCre-Pparb/d-/- and Pparb/dfl/fl with antioxidant N-acetyl-cysteine prior DSS-induced tumorigenesis resulted in lower tumor load. Gene expression analyses implicated an altered oxidative stress processes. Indeed, the FSPCre-Pparb/d-/- intestinal tumors have reduced oxidative stress than Pparb/dfl/fl tumors. Similarly, the colorectal cancer cells and human colon epithelial cells also experienced lower oxidative stress when co-cultured with fibroblasts depleted of PPARβ/δ expression. Therefore, our results establish a role for fibroblast PPARβ/δ in epithelial-mesenchymal communication for ROS homeostasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antioxidants / metabolism*
  • Cells, Cultured
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism
  • Fibroblasts / metabolism*
  • Gene Knockdown Techniques
  • HCT116 Cells
  • HT29 Cells
  • Humans
  • Mice
  • Mice, Knockout
  • PPAR delta / genetics*
  • PPAR-beta / genetics*
  • Reactive Oxygen Species / metabolism*
  • Reactive Oxygen Species / pharmacology*
  • Tumor Burden / drug effects*
  • Tumor Burden / genetics

Substances

  • Antioxidants
  • PPAR delta
  • PPAR-beta
  • Reactive Oxygen Species