Subepithelial myofibroblasts express cyclooxygenase-2 in colorectal tubular adenomas.
OBJECTIVE
Recent data support the hypothesis that the inducible isoform of cyclooxygenase (COX-2) plays a role in the early stages of colonic carcinogenesis and that nonsteroidal anti-inflammatory drugs (NSAIDs) retard the development of colon cancer by modulating COX-2. However, the cell types responsible for producing COX-2 in colorectal adenomas remain a subject of controversy.


METHODS
COX-2 expression in normal colonic mucosa (n = 50), hyperplastic polyps (n = 43), sporadic adenomas (n = 67), and invasive colonic adenocarcinoma (n = 39) was studied in formalin-fixed and paraffin-embedded tissue sections from endoscopy biopsy and colonic resection specimens. Immunohistochemistry (avidin-biotin complex technique with double immunolabeling) was used to identify the phenotypes of COX-2-producing cells.


RESULTS
In colorectal adenomas, increased expression of COX-2 was detected and localized to alpha smooth muscle actin ( proportional, variant SMA)-positive subepithelial stromal cells (myofibroblasts) in the periluminal region of the lamina propria in 63 (94%) of 67 cases. In contrast, in normal colonic mucosa and in hyperplastic polyps with intact epithelium, COX-2 expression was found only in macrophages and endothelial cells. In areas in which the surface epithelium was ulcerated in normal mucosa as well as hyperplastic or neoplastic polyps, COX-2 expression was increased in granulation tissue (and present in macrophages, endothelium, and myofibroblasts). In invasive carcinoma, COX-2 expression in myofibroblasts was limited to the adenomatous portion of the tumor and was detected in 62% of cases (n = 39). In addition, focal expression of COX-2 by malignant epithelial cells was observed in 23% of invasive adenocarcinoma.


CONCLUSIONS
These results show that increased COX-2 expression in sporadic adenoma of the colon is common and is localized specifically to subepithelial intestinal myofibroblasts. These findings further support the hypothesis that myofibroblasts are important target cells for NSAID-mediated chemoprevention of colorectal cancer.
Adegboyega
Patrick A
PA
Department of Pathology, 2190 John Sealy Annex, Mail Route 0588, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-0588, USA. paadegbo@utmb.edu
Ololade
Omiyosoye
O
Saada
Jamal
J
Mifflin
Randy
R
Di Mari
John F
JF
Powell
Don W
DW
D000199:Actins / Q000378:metabolism; D000230:Adenocarcinoma / Q000201:enzymology / Q000473:pathology; D000236:Adenoma / Q000201:enzymology* / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism; D003106:Colon / Q000201:enzymology; D015179:Colorectal Neoplasms / Q000201:enzymology* / Q000473:pathology; D051546:Cyclooxygenase 2; D004848:Epithelium / Q000201:enzymology*; D005260:Female; D005347:Fibroblasts / Q000201:enzymology*; D006801:Humans; D006965:Hyperplasia / Q000201:enzymology; D007124:Immunoenzyme Techniques; D007413:Intestinal Mucosa / Q000201:enzymology / Q000473:pathology; D007417:Intestinal Polyps / Q000201:enzymology / Q000473:pathology; D007527:Isoenzymes / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins; D008875:Middle Aged; D009130:Muscle, Smooth / Q000201:enzymology; D009361:Neoplasm Invasiveness; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D017154:Stromal Cells / Q000201:enzymology
D000199:Actins; D014408:Biomarkers, Tumor; D007527:Isoenzymes; D008565:Membrane Proteins; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases