Clinical features, treatment, and survival of patients with colorectal cancer with or without inflammatory bowel disease.

BACKGROUND & AIMS: Inflammatory bowel disease (IBD) increases the risk of colorectal cancer (CRC), indicating that inflammation might alter tumor characteristics and potentially affect treatment and survival. Published data on this topic are inconclusive, so we conducted a population-based study in Ireland to address it. METHODS: We used the National Cancer Registry to collect data on all patients diagnosed with CRC in Ireland from 1994 to 2005 (n = 22,335) and identified those who also had IBD (n = 170). The clinical characteristics, treatment, and survival of patients with IBD and CRC were compared with those of patients with CRC without IBD. RESULTS: Patients with CRC and IBD were, on average, 7.7 years younger than those without IBD at diagnosis of CRC (P = .001), and were less likely to smoke (P = .002). Fewer CRCs in patients with IBD were stage 4 at diagnosis (12% vs 22% in non-IBD patients; P < .001). There was no significant difference in CRC treatment modalities between patients with or without IBD (P = .57). The median survival time of CRC patients with IBD was about 3 years longer than that of patients without IBD (P < .001). However, Cox proportional hazards analysis revealed that IBD was not a significant prognostic factor for CRC (P = .97). However, older age, male sex, smoking, and advanced grade and stage all were associated independently with shorter survival time. When propensity score matching was used to analyze outcomes, the survival times of CRC patients with and without IBD did not differ significantly. CONCLUSIONS: The features of patients with CRC and IBD differ significantly from those of CRC patients without IBD, but each group of patients receive similar treatment and have similar patterns of disease progression after diagnosis.

Regulation of NF-kappaB responses by epigenetic suppression of IkappaBalpha expression in HCT116 intestinal epithelial cells.

Intestinal epithelial cells play critical roles in regulating mucosal immunity. Since epigenetic factors such as DNA methylation and histone modifications are implicated in aging, carcinogenesis, and immunity, we set out to assess any role for epigenetic factors in the regulation of intestinal epithelial cell immune responses. Experiments were conducted using the HCT116 cell line, and a subclone was genetically engineered to lack DNA methyltransferases (DNMT). The induction of the chemokine interleukin-8 and the antiapoptotic protein cFLIP by tumor necrosis factor-alpha were markedly less in HCT116 cells lacking DNMT than in parental cells. These effects were accompanied by lower monocyte chemotaxis and higher caspase signaling in HCT116 cells lacking DNMT than parental cells. Tumor necrosis factor-alpha-induced NF-kappaB activation was blocked and IkappaBalpha expression was higher in HCT116 cells lacking DNMT than in parental cells. A CpG island in the IkappaBalpha gene promoter region was found to contain variable levels of methylation in parental HCT116 cells. Chromatin immunoprecipitation analysis of histone proteins bound to the IkappaBalpha gene promoter revealed that higher levels of IkappaBalpha expression in HCT116 cells lacking DNMT compared with parental cells were accompanied by more chromatin marks permissive to gene transcription. These findings show that epigenetic factors influence the NF-kappaB system in intestinal epithelial cells, resulting in a previously unrecognized mechanism of innate immune regulation.

Effect of genetic deletion or pharmacological antagonism of tumor necrosis factor alpha on colitis-associated carcinogenesis in mice.

BACKGROUND: Intestinal inflammation in inflammatory bowel diseases is driven by abnormal levels of proinflammatory cytokines, where tumor necrosis factor (TNF)-α seems to be particularly important. Chronic inflammatory signaling in the colon increases the risk of colorectal cancer, so we sought to evaluate the role of TNF-α in a mouse model of this condition. METHODS: TNF mice were treated with azoxymethane/dextran sulfate sodium to induce inflammation and tumorigenesis. Etanercept was used to produce pharmacological ablation of TNF-α in wild-type mice. Subsequent activation of procarcinogenic transcription factor NF-κB and relevant proinflammatory cytokines of the TNF superfamily were measured through immunohistochemistry and quantitative polymerase chain reaction methods. RESULTS: Results showed that the severity of colitis, as assessed by mortality, histological scoring, and cytokine expression levels, was similar or slightly higher in mice lacking TNF-α than in control mice. Activation levels of NF-κB were not influenced by the presence of TNF-α. We also observed upregulated expression of TNF family member TNF-ß, TNF receptors 1 and 2 and a variety of other proinflammatory factors in colitis-associated tumors of TNF mice, compared with levels in tumors of control mice. Neither genetic ablation of TNF-α nor pharmacological inhibition of the TNF family using etanercept reduced tumor number. CONCLUSIONS: Our results reveal a redundant role for TNF-α in a mouse model of colitis-associated tumorigenesis, indicating a high degree of redundancy in proinflammatory cytokine networks in this model.

How to manage the risk of colorectal cancer in ulcerative colitis.

There is a strong association between chronic inflammation and cancer formation. This correlation has been well observed in patients with long standing inflammatory bowel disease (IBD) who are at high risk of colorectal cancer (CRC). At present, there is a lack of good markers for predicting the progression from normal to neoplastic mucosa in patients with IBD. IBD patients who are 'at-risk' of CRC should be identified, evaluated and should also be enrolled in surveillance program, regardless of their disease activity. Early identification of dysplasia and its appropriate management using endoscopic techniques or surgery are essential in patients with long-standing IBD, to minimize CRC morbidity and mortality. Gastroenterologists should work along with experienced, specialised gastrointestinal pathologists, surgeons and with fully informed and compliant IBD patients' to ensure the success of surveillance programme in early detection of CRC.