Localisation of cyclooxygenase-2 in sporadic colorectal adenomas

Research output: Contribution to journalArticle

Authors

  • K S Chapple
  • E J Cartwright
  • G Hawcroft
  • A Tisbury
  • N Scott
  • A C J Windsor
  • P Guillou
  • A F Markham
  • L Coletta
  • M Hull

Colleges, School and Institutes

Abstract

A putative target for the anti-colorectal cancer action of nonsteroidal anti-inflammatory drugs is the inducible isoform of cyclooxygenase (COX), COX-2. COX-2 is expressed within intestinal adenomas in murine polyposis models, but expression has been poorly characterized in human colorectal neoplasms. Therefore, we investigated the localization of the COX-2 protein in human sporadic colorectal adenomas. Immunohistochemistry for COX-2 and CD68 (a tissue macrophage marker) was performed on formalin-fixed, paraffin-embedded (n = 52) and frozen, acetone-fixed (n = 6) sections of human sporadic colorectal adenomas. Forty of 52 (77%) formalin-fixed adenomas expressed immunoreactive COX-2. COX-2 was localized to superficial interstitial macrophages in 39 cases (75%) and to deep interstitial macrophages in 9 cases (17%). COX-2 staining of dysplastic epithelial cells was observed in 15 cases (29%). A logistic regression analysis identified the adenoma site (P = 0.012) and histological type (P = 0.001) as independent predictors of superficial macrophage COX-2 expression. There was no relationship between the number of macrophages within an adenoma and macrophage COX-2 expression. These results indicate that COX-2 is expressed predominantly by interstitial macrophages within human sporadic colorectal adenomas. If COX-2 does indeed play a role in the early stages of colorectal carcinogenesis in man, these data suggest COX-2-mediated paracrine signaling between the macrophages and epithelial cells within adenomas.


A substantial body of evidence from epidemiological studies and animal models of intestinal tumorigenesis indicates that nonsteroidal anti-inflammatory drugs (NSAID) are effective chemopreventative agents against colorectal cancer. 1,2 The mechanism of the anti-neoplastic activity of NSAIDs remains unclear, but one possible route is via the inhibition of cyclooxygenase (COX). 3 Two isoforms of COX have been described: 4 COX-1, which is constitutively expressed in normal adult human tissues including the colon, 5-9 and an inducible isoform, COX-2, the expression of which is induced in cultured cells by cytokines and growth factors. 4 COX-2 is absent or expressed at low levels in the normal human colon. 5-8,10,11 However, COX-2 expression is up-regulated in 85 to 100% of human sporadic colorectal carcinomas, 5,6,10-13 predominantly within neoplastic epithelial cells, in which COX-2 may induce resistance to apoptosis, 14 alter extracellular matrix adhesion, 14 modulate tumor angiogenesis, 15 and increase metastatic potential. 16

COX-2 also plays an important role at an earlier stage of intestinal tumorigenesis. Within intestinal adenomas of Min and ApcΔ716 mouse models of familial adenomatous polyposis, Cox-2 is localized to interstitial cells, which have been identified as macrophages. 17-19 Disruption of Ptgs2 (the mouse COX-2 gene) and administration of the selective Cox-2 inhibitor, MF-tricyclic, in the ApcΔ716 mouse have both been shown to dramatically reduce intestinal adenoma development. 17

Although sporadic colorectal adenoma development and progression are potential targets for colorectal cancer chemoprevention, the expression of COX-2 in human sporadic colorectal adenomas has received little attention. Studies of small numbers of sporadic and familial adenomatous polyposis adenomas have produced variable results with the expression of COX-2 demonstrated in between 0 to 90% of the adenomas. 6,10,13,18,20 We, therefore, performed an immunohistochemical study of COX-2 protein expression and localization in a large series of human sporadic colorectal adenomas.

Details

Original languageEnglish
Pages (from-to)545–553
JournalThe American Journal of Pathology
Volume156
Issue number2
Publication statusPublished - Feb 2000

Keywords

  • cyclooxygenase-2 , colorectal adenomas