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Evidence is accumulating which indicates that cyclooxygenase-2 (COX-2) is involved in the pathogenesis of colorectal cancer. We evaluated the expression of COX-2 in replication error-positive (RER) colon cancers, colon cancers metastatic to liver and azoxymethane (AOM)-induced rat colonic tumors. Immunohistochemistry showed that COX-2 was low to undetectable in normal human mucosa, but abundant in the RER adenocarcinomas we examined. COX-2 immunoreactivity in metastatic colon cancers was less abundant, but clearly detectable. In the colon of AOM-treated rats, COX-2 protein was not detectable in normal mucosa, but present in most of the epithelial cells comprising the tumors. The TGF-β1 staining pattern in these human and rat tumors was similar to that observed for COX-2. The role of TGF-β in RER adenocarcinomas is complex because of the increased mutation rate of TGF-β type II receptors. Northern analysis showed abundant TGF-β1 mRNA in AOM-induced tumors, but not in paired mucosa. TGF-β1 induced the expression of COX-2 mRNA and protein in intestinal epithelial cells (IEC-6). Chronic TGF-β1 treatment caused a TGF-β-dependent overexpression of COX-2 in rat intestinal epithelial cells (RIE-1). TGF-β1 may regulate COX-2 expression during the colonic adenoma to carcinoma sequence. [ABSTRACT FROM PUBLISHER]

Cyclooxygenase-2 has been reported to play an important role in colorectal carcinogenesis. The effects of meloxicam (a COX-2 inhibitor) on the growth of two colon cancer cell lines that express COX-2 (HCA-7) and Moser-S) and a COX-2 negative cell line (HCT-116) were evaluated. The growth rate of these cells was measured following treatment with meloxicam. HCA-7 and Moser-S colony size were significantly reduced following treatment with meloxicam; however, there was no significant change in HCT-116 colony size with treatment. In vivo studies were performed to evaluate the effect of meloxicam on the growth of HCA-7 cells when xenografted into nude mice. We observed a 51% reduction in tumor size after 4 weeks of treatment. Analysis of COX-1 and COX-2 protein levels in HCA-7 tumor lysates revealed a slight decrease in COX-2 expression levels in tumors taken from mice treated with meloxicam and no detectable COX-1 expression. Here we report that meloxicam significantly inhibited HCA-7 colony and tumor growth but had no effect on the growth of the COX-2 negative HCT-116 cells. [ABSTRACT FROM PUBLISHER]

The physical interaction between β-catenin and the adenomatous polyposis coli (APC) gene, and the ability of APC to regulate cytoplasmic levels of β-catenin suggest a role for β-catenin in colorectal carcinogenesis. In this study, we found that β-catenin immunoreactivity was detected exclusively in the cell membrane and cytoplasm of morphologically normal intestinal epithelial cells with predominant distribution in the differentiated non-proliferative cell population. In contrast, β-catenin was localized predominantly in the nucleus of adenomas from Min/+ mice and transgenic mice expressing a mutant truncated form of the APC gene (ApcΔ716 mice). β-catenin was expressed predominantly at the cell membrane and cytoplasm of the nontransformed rat intestinal epithelial (RIE-1) cells in culture, whereas predominantly nuclear localization of β-catenin was observed in the human colon cancer cell line SW480. In the azoxymethane (AOM) treated rats, overexpression and nuclear localization of β-catenin was observed in all adenomas. Previous studies have indicated the incidence of APC mutations amongst AOM-induced tumors to be 15% or less. These results demonstrate that nuclear localization of β-catenin is a common event in colorectal tumorigenesis. [ABSTRACT FROM PUBLISHER]

Continuous use of nonsteroidal anti-inflammatory drugs (NSAIDs) lowers the relative risk of colorectal cancer in humans and decreases tumor yield in rodents treated with carcinogens. One well documented target for NSAIDs is prostaglandin endoperoxide synthase (cyclooxygenase) and two isoforms of this enzyme have been identified, cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). COX enzymes produce eicosanoid products, some of which have recently been shown to activate transcription mediated by the nuclear hormone receptor peroxisome proliferator activated receptor γ (PPARγ), whose expression is largely restricted to adipose tissue. The present study was undertaken to determine if PPARγ was expressed in colonic tumors. PPARγ messenger RNA (mRNA) and protein levels were assayed in colonic tumors and normal adjacent mucosa, as well as in a variety of human colon cancer cell lines. There was a marked increase in PPARγ RNA levels in four out of four of the colonic tumors compared to paired normal mucosa, where little expression of PPARγ was detected. Western blotting analysis showed that PPARγ protein was expressed in four out of five colonic tumor samples. PPARγ was also expressed in a subset of polyps, and in certain human colonic cancer cell lines as well. Additionally, we were able to demonstrate that an eicosanoid, 15 deoxy-Δ12,14 PGJ2, transactivated transcription of a PPRE-driven promoter in CaCo-2 cells. Thus, we have shown that PPARγ gene and protein expression is elevated in rodent colon tumors, in selected human colon cancer cell lines and that the PPARγ receptor is functional in CaCo-2 cells. Since PPARγ is a ligand-modulated transcription factor, it may provide a novel target for chemopreventive strategies for colorectal cancer. [ABSTRACT FROM PUBLISHER]