High expression of cyclooxygenase‐2 in macrophages of human colonic adenoma

Abstract

Cyclooxygenase (COX)-2 is a possible molecular target for suppression of colon carcinogenesis by non-steroidal antiinflammatory drugs (NSAIDs). However, the expression of COX-2 in human colonic tumors during the adenomacarcinoma sequence has not been elucidated. In the present study, we examined immuno-histochemically the expression and localization of the COX-2 protein in human colonic adenomas and cancers. Twelve human colonic adenomas and 9 advanced cancers were studied. Immunoreactive COX-2 was predominantly and strongly expressed in sub-epithelial interstitial cells broadly present in the surface area of adenomas. The staining pattern of macrophages was similar to that observed for COX-2 in adenomas. Adjacent normal colonic mucosa was negative for COX-2 expression. In contrast, COX-2 was relatively weakly expressed in both tumor cells and interstitial cells in advanced colon cancers. In conclusion, the target of NSAIDs in preventing colon carcinogenesis may be the COX-2 expressed in interstitial cells, possibly macrophages, of colonic adenomas. Int. J. Cancer 83:470-475, 1999. Wiley-Liss, Inc.Attention has focused on the hypothesis that non-steroidal anti-inflammatory drugs (NSAIDs) suppress colon carcinogenesis. Several lines of evidence from human and experimental animal studies support this hypothesis. In human epidemiological and clinical studies, NSAIDs decrease the incidence and mortality of colorectal cancer and induce regression of adenomas in patients with familial adenomatous polyposis (FAP). Experimental animal studies have shown that NSAIDs reduce the number and size of carcinogen-induced colon tumors (reviewed by DuBois et al., 1996a). In Apc Min mice (Su et al., 1992) with a germline mutation in Apc, a genetically manipulated animal model of colon cancer, NSAIDs were found to suppress the formation of intestinal tumors (Jacoby et al., 1996).The precise mechanism by which NSAIDs suppress colon carcinogenesis has not been elucidated. NSAIDs are known to inhibit cyclooxygenase (COX)

Mucin‐depleted foci show strong activation of inflammatory markers in 1,2‐dimethylhydrazine‐induced carcinogenesis and are promoted by the inflammatory agent sodium dextran sulfate

“…The increased expression of COX-2 in MDF is mostly due to stromal cells. Accordingly, we also found that macrophages (CD-68 positive cells) were present in the stroma pertaining to MDF, suggesting, as reported by others, 25,37,38 that these cells could contribute to COX-2 activity during colon carcinogenesis. Macrophage infiltration higher than that in normal mucosa was also found in tumours, but not in ACF.…”

“…6,7,9,24 Furthermore, studies in both humans and experimental animals demonstrate activation of inflammatory processes in colonic tumours. 8,21,25 AOM-induced colonic tumours show increased COX-2 expression 8,21,26 and several anti-inflammatory drugs which inhibit COX-2 activity also reduce colon carcinogenesis. 9,27,28 It has also been demonstrated that in colon tumours, as chronic inflammation, there is overexpression of inducible NOS (i-NOS), 23 producing nitric oxide (NO) implicated in DNA damage, COX-2 expression and macrophage-mediated immunity; a similar increase in i-NOS is also a common phenomenon during chronic inflammation.…”

EP1–4 subtype, COX and PPARγ receptor expression in colorectal cancer in prediction of disease‐specific mortality

“…Other considerations may be various infiltration of macrophages in tumors occasionally overexpressing COX-2, which would produce prostanoids with altered steady-state adaptation in various cell compartments of a growing tumor. 47,48 The role of prostanoids and immune cells in colon cancer is now under investigation in our laboratory.…”

Cytoplasmic phospholipase A2 alpha overexpression in stromal cells is correlated with angiogenesis in human colorectal cancer

“…In accordance with this finding, COX-2 expression has already been demonstrated in interstitial cells of human colon adenomas and carcinomas. 12,14,36 Some authors found that COX-2-positive interstitial cells correspond mainly to macrophages [10][11][12] but others demonstrate COX-2 expression mainly in fibroblasts. 13,14 Our results indicate that superficial fibroblasts and myofibroblasts may express cytoplasmic PLA2 as well as COX-2 and are thus in accordance with these latter studies.…”

“…[7][8][9] In colon adenomas and carcinomas, COX-2 is overexpressed in tumor cells but also in interstitial stromal cells. [10][11][12][13][14] COX-2 overexpression in interstitial stromal cells also induces tumor angiogenesis in several models of tumor development. 15,16 In intestinal tumors, angiogenesis induced by COX-2 expressing interstitial stromal cells is mediated by prostaglandin E2 through EP2 prostaglandin E2 receptor signaling.…”