We previously reported that colon carcinomas, adenomas, and hyperplastic polyps exhibiting a serrated histology were very likely to possess BRAF mutations, whereas when these same advanced colonic lesions exhibited non-serrated histology, they were wild type for BRAF; among hyperplastic polyps, KRAS mutations were found mainly in a non-serrated variant. On this basis, we predicted that hyperplastic aberrant crypt foci (ACF), a putative precancerous lesion found in the colon, exhibiting a serrated phenotype would also harbor BRAF mutations and that non-serrated ACF would not. In contrast, KRAS mutations would be found more often in the nonserrated ACF. We examined 55 ACF collected during screening colonoscopy from a total of 28 patients. Following laser capture microdissection, DNA was isolated, and mutations in BRAF and KRAS were determined by direct PCR sequencing. When hyperplastic lesions were further classified into serrated and non-serrated histologies, there was a strong inverse relationship between BRAF and KRAS mutations: a BRAF V600E mutation was identified in 10 of 16 serrated compared with 1 of 33 non-serrated lesions (P = 0.001); conversely, KRAS mutations were present in 3 of 16 serrated compared with 14 of 33 non-serrated lesions. Our finding of a strong association between BRAF mutations and serrated histology in hyperplastic ACF supports the idea that these lesions are an early, sentinel, or a potentially initiating step on the serrated pathway to colorectal carcinoma. [Cancer Res 2007;67(8):3551-4]

Recent studies suggest that secreted phospholipases A 2 (sPLA 2 s) represent attractive potential tumour biomarkers and therapeutic targets for various cancers. As a first step to address this issue in human colorectal cancer, we examined the expression of the full set of sPLA 2 s in sporadic adenocarcinomas and normal matched mucosa from 21 patients by quantitative PCR and immunohistochemistry. In normal colon, PLA2G2A and PLA2G12A were expressed at high levels, PLA2G2D, PLA2G5, PLA2G10 and PLA2G12B at moderate levels, and PLA2G1B, PLA2G2F and PLA2G3 at low levels. In adenocarcinomas from left and right colon, the expression of PLA2G3 was increased by up to 40-fold, while that of PLA2G2D and PLA2G5 was decreased by up to 23-and 14-fold. The variations of expression for sPLA 2 -IID, sPLA 2 -III and sPLA 2 -V were confirmed at the protein level. The expression pattern of these sPLA 2 s appeared to be linked respectively to the overexpression of interleukin-8, defensin a6, survivin and matrilysin, and downregulation of SFRP-1 and RLPA-1, all these genes being associated to colon cancer. This original sPLA 2 profile observed in adenocarcinomas highlights the potential role of certain sPLA 2 s in colon cancer and suggests that sPLA 2 -III might be a good candidate as a novel biomarker for both left and right colon cancers.

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Nonselective cyclooxygenase (COX) inhibitors target many of the same cancer-associated molecular pathways as COX-2-specific inhibitors. Although these nonsteroidal anti-inflammatory drugs (NSAIDs) are often associated with gastrointestinal toxicity, there is renewed interest in their use as colorectal cancer (CRC) chemopreventive agents due to the adverse side effects associated with long-term use of selective COX-2 inhibitors. In this study, we investigated the effects of long-term use (up to 25 years) of NSAIDs (ibuprofen or aspirin) on adenoma pathology and b-catenin-mediated signaling in sporadic human colon adenomas. Although NSAID use did not impact overall adenoma size or degree of dysplasia, it did cause a significant inhibition of nuclear b-catenin localization, which correlated with suppression of cyclin D1 expression. To further elucidate the effect of these agents in regulating b-catenin, we treated SW480 colon cancer cells with a panel of NSAIDs and determined their effects on b-catenin levels and cellular localization. In agreement with our in vivo results, both S-ibuprofen and aspirin were found to decrease total levels of b-catenin while increasing its phosphorylation. In addition, S-ibuprofen induced both degradation of IkBa and nuclear localization of NF-kB. Despite its nuclear localization, however, the activation of the NF-kB target genes, Bcl-2, survivin, and cyclin D1, was suppressed. This reduction in NF-kB transcriptional activity may be due to increased phosphorylation of GSK-3b following S-ibuprofen treatment. These data suggest that ibuprofen can effectively target both the Wnt/b-catenin and NF-kB pathways, and potentially uncovers a novel mechanism through which NSAIDS may exert their chemopreventive efficacy.