NF-kappaB, p38 MAPK and JNK are highly expressed and active in the stroma of human colonic adenomatous polyps

Abstract

The factors that govern the progression from colonic adenomatous polyp to colon cancer are poorly understood. The observation that NSAIDs act as chemopreventative agents and reduce the size of colonic polyps suggests the involvement of in¯ammatory signalling, but in¯ammatory signalling in colonic polyps has not been studied. We investigated the expression of the active forms of NF-kB, JNK and p38 MAPK using immunohistochemistry with activation speci®c antibodies in human colonic adenomas. We show that active NF-kB is seen in stromal macrophages that also express COX-2 and TNF-a, active JNK is seen in stromal and intraepithelial T-lymphocytes and periendothelial cells of new blood vessels, and active p38 MAPK is most highly expressed in macrophages and other stromal cells. These results demonstrate the presence of active in¯ammatory signal transduction in colonic polyps and that these are predominantly in the stroma. In the case of NF-kB this coincides with the cellular localisation of COX-2. These results support evidence that NSAIDs may act through e ects on stromal cells rather than epithelial cells. Oncogene (2001) 20, 819 ± 827.

Evidence for colorectal cancer cell specificity of aspirin effects on NFκB signalling and apoptosis

“…Increased NFkB activity has been observed in CRC (Hardwick et al, 2001) and relative resistance to apoptosis has been attributed to high constitutive NFkB activity in other cancers (Bours et al, 1994;Lind et al, 2001;Charalambous et al, 2003). However, we found no evidence that the specificity of the aspirin-NFkB response is related to differential expression of basal IkBa or p65 proteins or their relative expression.…”

Paracrine cyclooxygenase-2-mediated signalling by macrophages promotes tumorigenic progression of intestinal epithelial cells

“…In keeping with these observations, increased epithelial cell COX-2 expression in primary colorectal cancers has been associated with reduced patient survival (Sheehan et al, 1999). However, at an earlier stage of carcinogenesis, in benign human colorectal adenomas or polyps (which represent a more relevant target for chemoprevention), COX-2 is expressed predominantly by stromal cells (as well as by dysplastic epithelial cells), the majority of which have been identified as CD68-positive inflammatory mononuclear cells or macrophages (Bamba et al, 1999;Muller-Decker et al, 1999;Chapple et al, 2000;Hull et al, 2000b;Soslow et al, 2000;Hardwick et al, 2001;Khan et al, 2001;Takeuchi et al, 2002). A similar pattern of COX-2 expression has also been noted in tumours from several murine intestinal tumorigenesis models (Oshima et al, 1996;Taketo, 1998;Hull et al, 1999;Shattuck-Brandt et al, 1999, although there appears to be increased heterogeneity in the COX-2-expressing stromal cell population in mice compared with humans (Taketo, 1998;Hull et al, 1999;Shattuck-Brandt et al, 1999.…”

Intracellular colon cancer-associated Escherichia coli promote protumoral activities of human macrophages by inducing sustained COX-2 expression

“…29 High expression of active MAPKs has been observed in the stroma of human colonic adenomatous polyps. 61 Involvement of MAPK signaling pathways in induction of COX-2 expression by colon cancer-associated E. coli was revealed by decrease in COX-2 level upon selective inhibition of these signaling pathways. Involvement of pro-inflammatory signaling pathways in COX-2 transcriptional induction by pathogens has been previously reported.…”

“…Increased levels of COX-2 in macrophages have been reported in human CRC and mouse models of CRC. 39,[58][59][60][61] COX-2 expression is regulated at both the transcriptional and posttranscriptional levels, and the signaling pathways involved in COX-2 transcriptional regulation include NF-kB, PI3K/AKT, GSK/b-catenin, and MAPKs. 29 High expression of active MAPKs has been observed in the stroma of human colonic adenomatous polyps.…”