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/d(fl/fl) mice. The pre-treatment of FSPCre-Pparb/d(-/-) and Pparb/d(fl/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/d(fl/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.