The role of the gastrointestinal microbiota in colorectal cancer

Both environmental and genetic factors contribute to cancers of the gastrointestinal tract including, the stomach, colon and rectum. The mechanisms associated with gastrointestinal cancer causation and prevention are largely unknown and the subject of much research. Many of the proposed mechanisms implicate the metabolic activities of the bacterial biota normally resident in the gastrointestinal tract. This review examines both the adverse and beneficial consequences of bacterial activity of the gastrointestinal tract focusing, in particularly on the stomach and large intestine. Studies on the role of the bacterial biota in colon carcinogenesis have also resulted in several useful biomarkers for use in human.

Dietary, lifestyle and clinico-pathological factors associated with APC mutations and promoter methylation in colorectal cancers from the EPIC-Norfolk Study

The tumour suppressor APC is the most commonly altered gene in colorectal cancer (CRC). Genetic and epigenetic alterations of APC may therefore be associated with dietary and lifestyle risk factors for CRC. Analysis of APC mutations in the extended mutation cluster region (codons 1276-1556) and APC promoter 1A methylation was performed on 185 archival CRC samples collected from participants of the European Prospective Investigation into Cancer (EPIC)-Norfolk Study, with the aim of relating these to high quality seven-day dietary and lifestyle data collected prospectively. Truncating APC mutations (APC+) and promoter 1A methylation (PM+) were identified in 43% and 23% of CRCs analysed, respectively. Distal CRCs were more likely than proximal CRCs to be APC+ or PM+ (P = 0.04). APC+ CRCs were more likely to be moderately/well differentiated and microsatellite stable than APC- CRCs (P = 0.05 and 0.03). APC+ CRC cases consumed more alcohol than their counterparts (P = 0.01) and PM+ CRC cases consumed lower levels of folate and fibre (P = 0.01 and 0.004). APC+ or PM+ CRC cases consumedhigher levels of processed meat and iron from red meat and red meat products (P=0.007 and 0.006). Specifically, CRC cases harbouring GC to AT transition mutations consumed higher levels of processed meat (35 versus 24 g/day, P = 0.04) and iron from red meat and red meat products (0.8 versus 0.6 mg/day, P = 0.05). In a logistic regression model adjusted for age, sex and cigarette smoking status, each 19g/day (1SD) increment increase in processed meat consumption was associated with cases with GC to AT mutations (OR 1.68, 95% CI 1.03-2.75). In conclusion, APC+ and PM+ CRCs may be influenced by diet and GC to AT mutations in APC are associated with processed meat consumption, suggesting a mechanistic link with dietary alkylating agents, such as N-nitroso compounds.

Phytoestrogen consumption and association with breast, prostate and colorectal cancer in EPIC Norfolk

Phytoestrogens are polyphenolic secondary plant metabolites that have structural and functional similarities to 17β-oestradiol and have been associated with a protective effect against hormone-related cancers. Most foods in the UK only contain small amounts of phytoestrogens (median content 21 μg/100 g) and the highest content is found in soya and soya-containing foods. The highest phytoestrogen content in commonly consumed foods is found in breads (average content 450 μg/100 g), the main source of isoflavones in the UK diet. The phytoestrogen consumption in cases and controls was considerably lower than in Asian countries. No significant associations between phytoestrogen intake and breast cancer risk in a nested case-control study in EPIC Norfolk were found. Conversely, colorectal cancer risk was inversely associated with enterolignan intake in women but not in men. Prostate cancer risk was positively associated with enterolignan intake, however this association became non-significant when adjusting for dairy intake, suggesting that enterolignans can act as a surrogate marker for dairy or calcium intake.

Review of the evidence for a colorectal cancer screening programme in elderly people.

Colorectal cancer is a major public health issue, contributing to 16,000 UK deaths per year, most of these in the elderly population. A new NHS screening programme for colorectal cancer in people over 60 is being introduced across the country throughout 2009. The aim of this research was to review the current literature on colorectal cancer screening and determine how much of the evidence for screening is applicable to elderly people. MEDLINE database was searched for articles published between 1990 and 2007, using search terms of colorectal neoplasms, mass-screening, faecal occult blood, colonoscopy and sigmoidoscopy. Articles for inclusion were limited to those in English and those including older adults. The results showed that evidence for colorectal cancer screening in general has been well researched. However, little was found specifically on screening for elderly people, or looking at the different benefits and limitations in older people compared to younger people. Very few health agencies suggested an upper age limit for screening. In conclusion, there is very little research on screening for colorectal cancer specifically in elderly people, although many health authorities advise such screening. The health needs of an older population are different to those of middle-aged people and at present the screening programmes do not appear to reflect this.

In vitro and in vivo models of colorectal cancer: antigenotoxic activity of berries.

The etiology of colorectal cancer (CRC), a common cause of cancer-related mortality globally, has strong associations with diet. There is considerable epidemiological evidence that fruits and vegetables are associated with reduced risk of CRC. This paper reviews the extensive evidence, both from in vitro studies and animal models, that components of berry fruits can modulate biomarkers of DNA damage and that these effects may be potentially chemoprotective, given the likely role that oxidative damage plays in mutation rate and cancer risk. Human intervention trials with berries are generally consistent in indicating a capacity to significantly decrease oxidative damage to DNA, but represent limited evidence for anticarcinogenicity, relying as they do on surrogate risk markers. To understand the effects of berry consumption on colorectal cancer risk, future studies will need to be well controlled, with defined berry extracts, using suitable and clinically relevant end points and considering the importance of the gut microbiota.

N-nitroso compound exposure-associated transcriptomic profiles are indicative of an increased risk for colorectal cancer

Endogenous formation of N-nitroso compounds (NOCs), which are known animal carcinogens, could contribute to human carcinogenesis but definitive evidence is still lacking. To investigate the relevance of NOCs in human colorectal cancer (CRC) development, we analyzed whole genome gene expression modifications in human colon biopsies in relation to fecal NOC exposure. We had a particular interest in patients suffering from intestinal inflammation as this may stimulate endogenous NOC formation, and consequently predispose to CRC risk. Inflammatory bowel disease (IBD) patients diagnosed with ulcerative colitis and irritable bowel syndrome patients without inflammation, serving as controls, were therefore recruited. Fecal NOC were demonstrated in the majority of subjects. By associating gene expression levels of all subjects to fecal NOC levels, we identified a NOC exposure-associated transcriptomic response that suggests that physiological NOC concentrations may potentially induce genotoxic responses and chromatin modifications in human colon tissue, both of which are linked to carcinogenicity. In a network analysis, chromatin modifications were linked to 11 significantly modulated histone genes, pointing towards a possible epigenetic mechanism that may be relevant in comprehending NOC-induced carcinogenesis. In addition, pro-inflammatory transcriptomic modifications were identified in visually non-inflamed regions of the IBD colon. However, fecal NOC levels were slightly but not significantly increased in IBD patients, suggesting that inflammation did not strongly stimulate NOC formation. We conclude that NOC exposure is associated with gene expression modifications in the human colon that may suggest a potential role of these compounds in CRC development.

Diallyl disulphide, a beneficial component of garlic oil, causes a redistribution of cell-cycle growth phases, induces apoptosis and enhances butyrate-induced apoptosis in colorectal adenocarcinoma cells (HT-29)

Colon cancer is a leading and expanding cause of death worldwide. A major contributory factor to this disease is diet composition; some components are beneficial (e.g. dietary fibre) whilst others are detrimental (e.g. alcohol). Garlic oil is a prominent dietary constituent that prevents the development of colorectal cancer. This effect is believed to be mainly due to diallyl disulphide (DADS), which selectively induces redox stress in cancerous (rather than normal) cells which leads to apoptotic cell death. However, the detailed mechanism by which DADS causes apoptosis remains unclear. We show that DADS-treatment of colonic adenocarcinoma cells (HT-29) initiates a cascade of molecular events characteristic of apoptosis. These include a decrease in cellular proliferation, translocation of phosphatidylserine to the plasma-membrane outer-layer, activation of caspase-3, genomic-DNA fragmentation and G2/M phase cell-cycle arrest. Short-chain fatty acids (SCFAs), particularly butyrate (abundantly produced in the gut by bacterial fermentation of dietary polysaccharides), enhance colonic cell integrity but, in contrast, inhibit colonic-cancer cell growth. Combining DADS with butyrate augmented the effect of butyrate on HT-29 cells. These results suggest that the anti-cancerous properties of DADS afford greater benefit when supplied with other favourable dietary factors (SCFA/polysaccharides) that likewise reduce colonic tumour development.

Treatment of the elderly colorectal cancer patient: SIOG expert recommendations.

Colorectal cancer (CRC) is one of the commonest malignancies of Western countries, with approximately half the incidence occurring in patients >70 years of age. Elderly CRC patients, however, are understaged, undertreated and underrepresented in clinical trials. The International Society of Geriatric Oncology created a task force with a view to assessing the potential for developing guidelines for the treatment of elderly (geriatric) CRC patients. A review of the evidence presented by the task force members confirmed the paucity of clinical trial data in elderly people and the lack of evidence-based guidelines. However, recommendations have been proposed on the basis of the available data and on the emerging evidence that treatment outcomes for fit, elderly CRC patients can be similar to those of younger patients. It is hoped that these will pave the way for formal treatment guidelines based upon solid scientific evidence in the future.

Components of olive oil and chemoprevention of colorectal cancer

Olive oil contains a vast range of substances such as monounsaturated free fatty acids (e.g., oleic acid), hydrocarbon squalene, tocopherols, aroma components, and phenolic compounds. Higher consumption of olive oil is considered the hallmark of the traditional Mediterranean diet, which has been associated with low incidence and prevalence of cancer, including colorectal cancer. The anticancer properties of olive oil have been attributed to its high levels of monounsaturated fatty acids, squalene, tocopherols, and phenolic compounds. Nevertheless, there is a growing interest in studying the role of olive oil phenolics in carcinogenesis. This review aims to provide an overview of the relationship between olive oil phenolics and colorectal cancer, in particular summarizing the epidemiologic, in vitro, cellular, and animal studies on antioxidant and anticarcinogenic effects of olive oil phenolics.

Colorectal cancer and the relationship between genes and the environment

Colorectal cancer (CRC) is a significant cause of morbidity and mortality in developed countries, with both genetic and environmental factors contributing to the etiology and progression of the disease. Several risk factors have been identified, including positive family history, red meat intake, smoking, and alcohol intake. Protective factors include vegetables, calcium, hormone replacement therapy, folate, nonsteroidal anti-inflammatory drugs, and physical activity. The interaction between these environmental factors, in particular diet and genes, is an area of growing interest. Currently, oncogenes, tumor suppressor genes, and mismatch repair genes are believed to play an essential role in colorectal carcinogenesis. When considering the genetics of CRC, only 10% of cases are inherited and only 2-6% can be ascribed to the highly penetrant genes, such as APC, hMLH and hMSH2. Lower penetrance genes combined with a Western-style diet contribute to the majority of sporadic CRCs. The purpose of this article is to give a brief overview of the epidemiologic studies that have been conducted and present the major findings. Here, we examine the molecular events in CRC, with particular focus on the interaction between genes and environment, and review the most current research in this area.

Transcriptomics and proteomics show that selenium affects inflammation, ctoskeleton, and cancer pathways in human rectal biopsies

Epidemiologic studies highlight the potential role of dietary selenium (Se) in colorectal cancer prevention. Our goal was to elucidate whether expression of factors crucial for colorectal homoeostasis is affected by physiologic differences in Se status. Using transcriptomics and proteomics followed by pathway analysis, we identified pathways affected by Se status in rectal biopsies from 22 healthy adults, including 11 controls with optimal status (mean plasma Se = 1.43 μM) and 11 subjects with suboptimal status (mean plasma Se = 0.86 μM). We observed that 254 genes and 26 proteins implicated in cancer (80%), immune function and inflammatory response (40%), cell growth and proliferation (70%), cellular movement, and cell death (50%) were differentially expressed between the 2 groups. Expression of 69 genes, including selenoproteins W1 and K, which are genes involved in cytoskeleton remodelling and transcription factor NFκB signaling, correlated significantly with Se status. Integrating proteomics and transcriptomics datasets revealed reduced inflammatory and immune responses and cytoskeleton remodelling in the suboptimal Se status group. This is the first study combining omics technologies to describe the impact of differences in Se status on colorectal expression patterns, revealing that suboptimal Se status could alter inflammatory signaling and cytoskeleton in human rectal mucosa and so influence cancer risk.

Peptides generated ex vivo from serum proteins by tumor-specific exopeptidases are not useful biomarkers in ovarian cancer

BACKGROUND: The serum peptidome may be a valuable source of diagnostic cancer biomarkers. Previous mass spectrometry (MS) studies have suggested that groups of related peptides discriminatory for different cancer types are generated ex vivo from abundant serum proteins by tumor-specific exopeptidases. We tested 2 complementary serum profiling strategies to see if similar peptides could be found that discriminate ovarian cancer from benign cases and healthy controls. METHODS: We subjected identically collected and processed serum samples from healthy volunteers and patients to automated polypeptide extraction on octadecylsilane-coated magnetic beads and separately on ZipTips before MALDI-TOF MS profiling at 2 centers. The 2 platforms were compared and case control profiling data analyzed to find altered MS peak intensities. We tested models built from training datasets for both methods for their ability to classify a blinded test set. RESULTS: Both profiling platforms had CVs of approximately 15% and could be applied for high-throughput analysis of clinical samples. The 2 methods generated overlapping peptide profiles, with some differences in peak intensity in different mass regions. In cross-validation, models from training data gave diagnostic accuracies up to 87% for discriminating malignant ovarian cancer from healthy controls and up to 81% for discriminating malignant from benign samples. Diagnostic accuracies up to 71% (malignant vs healthy) and up to 65% (malignant vs benign) were obtained when the models were validated on the blinded test set. CONCLUSIONS: For ovarian cancer, altered MALDI-TOF MS peptide profiles alone cannot be used for accurate diagnoses.

Oestrogenic and androgenic activity of triclosan in breast cancer cells

As a consequence of its widespread use as an antimicrobial agent in consumer goods, triclosan has become distributed ubiquitously across the ecosystem, and recent reports that it can cause endocrine disruption in aquatic species has increased concern. It is reported here that triclosan possesses intrinsic oestrogenic and androgenic activity in a range of assays in vitro which could provide some explanation for the endocrine disrupting properties described in aquatic populations. In terms of oestrogenic activity, triclosan displaced [H-3]oestradiol from oestrogen receptors (ER) of MCF7 human breast cancer cells and from recombinant human ER alpha/ER beta. Triclosan at 10(-5) M completely inhibited the induction of the oestrogen-responsive ERE-CAT reporter gene in MCF7 cells by 10(-10) M 17 beta-oestradiol and the stimulation of growth of MCF7 human breast cancer cells by 10(-10) M 17 beta-oestradiol. On its own, 1 mu M triclosan increased the growth of MCF7 cells over 21 days. Triclosan also had androgenic activity. It displaced [H-3]testosterone from binding to the ligand binding domain of the rat androgen receptor (AR). Triclosan was able to inhibit the induction of the androgen-responsive LTR-CAT reporter gene in S115 mouse mammary tumour cells by 10(-9) M testosterone and in T47D human breast cancer cells by 10(-8) M testosterone at concentrations of 10(-7) M and 10(-6) M, respectively. Triclosan at 2 x 10(-5) M antagonized the stimulation of the growth of S115+A mouse mammary tumour cells by 10(-9) M testosterone. The finding that triclosan has oestrogenic and androgenic activity warrants further investigation in relation to both endocrine disruption of aquatic wildlife and any possible impact on human health. Copyright (C) 2007 John Wiley & Sons, Ltd.