ROS release by PPAR?/?-null fibroblasts reduces tumor load through epithelial antioxidant response.

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 PPAR?/? 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 PPAR?/?, 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 PPAR?/? expression. Therefore, our results establish a role for fibroblast PPAR?/? in epithelial-mesenchymal communication for ROS homeostasis.

SUBMITTER: Tan EHP 

PROVIDER: S-EPMC5895604 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature