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 PPARgamma, COX-2 and p-IkB-alpha--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/alpha-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 PPARgamma, COX-2 and p-IkB-alpha only in colon adenocarcinomas (77.7%, 100% and 100% of cases, respectively) and not in normal colon. COX-2 and p-IkB-alpha expressions were strongly correlated in these cells (P < 0.001). PPARgamma, COX-2 and p-IkB-alpha 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 PPARgamma ligands may exert their chemoprophylactic properties through direct actions on these cells.