PPAR-gamma is expressed and NF-kB pathway is activated and correlates positively with COX-2 expression in stromal myofibroblasts surrounding colon adenocarcinomas.
OBJECTIVE
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.
Vandoros
Gerasimos P
GP
Department of Anatomy and Histology-Embryology, School of Medicine, University of Patras, Patras, Greece.
Konstantinopoulos
Panagiotis A
PA
Sotiropoulou-Bonikou
Georgia
G
Kominea
Athina
A
Papachristou
Georgios I
GI
Karamouzis
Michalis V
MV
Gkermpesi
Maria
M
Varakis
Ioannis
I
Papavassiliou
Athanasios G
AG
D000230:Adenocarcinoma / Q000737:chemistry*; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000378:metabolism; D003110:Colonic Neoplasms / Q000737:chemistry*; D051546:Cyclooxygenase 2 / Q000032:analysis*; D042783:Endothelial Cells / Q000737:chemistry; D005260:Female; D005347:Fibroblasts / Q000737:chemistry; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008264:Macrophages / Q000737:chemistry; D008297:Male; D008565:Membrane Proteins / Q000032:analysis*; D032342:Muscle Cells / Q000737:chemistry; D016328:NF-kappa B / Q000378:metabolism*; D047495:PPAR gamma / Q000032:analysis*; D015398:Signal Transduction
D014408:Biomarkers, Tumor; D008565:Membrane Proteins; D016328:NF-kappa B; D047495:PPAR gamma; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human