PPAR-gamma is expressed and NF-kB pathway is activated and correlates positively with COX-2 expression in stromal myofibroblasts surrounding colon adenocarcinomas

Purpose: Accumulated evidence indicates that carcinogenesis is closely associated with the transformation of normal stroma into a ‘reactive’ stromal phenotype. The present study investigated the role of PPARγ, COX-2 and p-IkB-α—important molecular targets of colon cancer chemoprevention—in this stromal remodeling by evaluating and comparing the expression of these factors in stromal myofibroblasts, macrophages and endothelial cells that surround normal colonic mucosa and colon cancer. Methods: Immunohistochemical methodology was employed on archived paraffin-embedded sections prepared from tumors and adjacent normal colon from 45 patients with colon adenocarcinomas. Double immunostaining with the universal marker for myofibroblasts (alpha-smooth muscle actin/α-SMA) as second primary antibody was also performed. Results: Stromal macrophages and endothelial cells expressed these factors both in normal colonic mucosa and colon cancer. By contrast, stromal myofibroblasts expressed PPARγ, COX-2 and p-IkB-α only in colon adenocarcinomas (77.7%, 100% and 100% of cases, respectively) and not in normal colon. COX-2 and p-IkB-α expressions were strongly correlated in these cells (P<0.001). PPARγ, COX-2 and p-IkB-α expression did not correlate with the stage or differentiation of the adenocarcinomas. Conclusions: NF-kB pathway is activated and COX-2 expression is upregulated in stromal myofibroblasts surrounding colon adenocarcinomas compared to normal colon. Induction of COX-2 expression is primarily induced by NF-kB. NSAIDs, selective COX-2 inhibitors and PPARγ ligands may exert their chemoprophylactic properties through direct actions on these cells.