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      Red and processed meat consumption and colorectal cancer risk: a systematic review and meta-analysis

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          Abstract

          The associations between red and processed meat consumption and the risk of colorectal cancer types have not been conclusively defined. We performed a systematic review and meta-analysis to analyze these associations. We searched PubMed and EMBASE to identify studies published from inception through September 2016. Dose-response, subgroup and subtype analyses of colorectal cancer (colon cancer, proximal colon cancer, distal colon cancer and rectal cancer) were performed. We ultimately selected 60 eligible studies. Positive associations were observed for colorectal cancer in case-control studies (red meat, P<0.01; processed meat, P<0.01) and cohort studies (red meat, P<0.01; processed meat, P<0.01). However, subtype analyses yielded null results for distal colon cancer in case-control studies ( P=0.41) and cohort studies ( P=0.18) for red meat and null results for proximal colon cancer in case-control studies ( P=0.13) and cohort studies ( P=0.39) for processed meat. Additionally, although the results of case-control studies were positive (red meat, P<0.01; processed meat, P=0.04) for rectal cancer, there were no positive associations between red ( P=0.34) and processed meat ( P=0.06) consumption and the risk in cohort studies. In a systematic review and meta-analysis, we found consumption of red and processed meat was associated with the risk of overall colorectal cancer but not rectal cancer. Additionally, there were no associations between the consumption of red meat and distal colon cancer risk and between the consumption of processed meat and proximal colon cancer risk.

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          Most cited references15

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          A red meat-derived glycan promotes inflammation and cancer progression.

          A well known, epidemiologically reproducible risk factor for human carcinomas is the long-term consumption of "red meat" of mammalian origin. Although multiple theories have attempted to explain this human-specific association, none have been conclusively proven. We used an improved method to survey common foods for free and glycosidically bound forms of the nonhuman sialic acid N-glycolylneuraminic acid (Neu5Gc), showing that it is highly and selectively enriched in red meat. The bound form of Neu5Gc is bioavailable, undergoing metabolic incorporation into human tissues, despite being a foreign antigen. Interactions of this antigen with circulating anti-Neu5Gc antibodies could potentially incite inflammation. Indeed, when human-like Neu5Gc-deficient mice were fed bioavailable Neu5Gc and challenged with anti-Neu5Gc antibodies, they developed evidence of systemic inflammation. Such mice are already prone to develop occasional tumors of the liver, an organ that can incorporate dietary Neu5Gc. Neu5Gc-deficient mice immunized against Neu5Gc and fed bioavailable Neu5Gc developed a much higher incidence of hepatocellular carcinomas, with evidence of Neu5Gc accumulation. Taken together, our data provide an unusual mechanistic explanation for the epidemiological association between red meat consumption and carcinoma risk. This mechanism might also contribute to other chronic inflammatory processes epidemiologically associated with red meat consumption.
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            A central role for heme iron in colon carcinogenesis associated with red meat intake.

            Epidemiology shows that red and processed meat intake is associated with an increased risk of colorectal cancer. Heme iron, heterocyclic amines, and endogenous N-nitroso compounds (NOC) are proposed to explain this effect, but their relative contribution is unknown. Our study aimed at determining, at nutritional doses, which is the main factor involved and proposing a mechanism of cancer promotion by red meat. The relative part of heme iron (1% in diet), heterocyclic amines (PhIP + MeIQx, 50 + 25 μg/kg in diet), and NOC (induced by NaNO₂+ NaNO₂; 0.17 + 0.23 g/L of drinking water) was determined by a factorial design and preneoplastic endpoints in chemically induced rats and validated on tumors in Min mice. The molecular mechanisms (genotoxicity, cytotoxicity) were analyzed in vitro in normal and Apc-deficient cell lines and confirmed on colon mucosa. Heme iron increased the number of preneoplastic lesions, but dietary heterocyclic amines and NOC had no effect on carcinogenesis in rats. Dietary hemoglobin increased tumor load in Min mice (control diet: 67 ± 39 mm²; 2.5% hemoglobin diet: 114 ± 47 mm², P = 0.004). In vitro, fecal water from rats given hemoglobin was rich in aldehydes and was cytotoxic to normal cells, but not to premalignant cells. The aldehydes 4-hydroxynonenal and 4-hydroxyhexenal were more toxic to normal versus mutated cells and were only genotoxic to normal cells. Genotoxicity was also observed in colon mucosa of mice given hemoglobin. These results highlight the role of heme iron in the promotion of colon cancer by red meat and suggest that heme iron could initiate carcinogenesis through lipid peroxidation. .
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              Mechanisms Linking Colorectal Cancer to the Consumption of (Processed) Red Meat: A Review.

              Colorectal cancer (CRC) is the third most commonly diagnosed cancer in the world. The vast majority of CRC cases have been linked to environmental causes rather than to heritable genetic changes. Over the last decades, epidemiological evidence linking the consumption of red and, more convincingly, of processed red meat to CRC has accumulated. In parallel, hypotheses on carcinogenic mechanisms underlying an association between CRC and the intake of red and processed red meat have been proposed and investigated in biological studies. The hypotheses that have received most attention until now include (1) the presence of polycyclic aromatic hydrocarbons and heterocyclic aromatic amines, two groups of compounds recognized as carcinogenic, (2) the enhancing effect of (nitrosyl)heme on the formation of carcinogenic N-nitroso compounds and lipid peroxidation. However, none of these hypotheses completely explains the link between red and processed red meat intake and the CRC risk. Consequently, scientists have proposed additional mechanisms or refined their hypotheses. This review first briefly summarizes the development of CRC followed by an in-depth overview and critical discussion of the different potential carcinogenic mechanisms underlying the increased CRC risk associated with the consumption of red and processed red meat.
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                Author and article information

                Journal
                Oncotarget
                Oncotarget
                Oncotarget
                ImpactJ
                Oncotarget
                Impact Journals LLC
                1949-2553
                10 October 2017
                6 September 2017
                : 8
                : 47
                : 83306-83314
                Affiliations
                1 Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, Xi′an, China
                2 Department of Obstetrics, Northwestern Women and Children’s Hospital, Xi′an, China
                3 Department of General Surgery, Chinese PLA 323 Hospital, Xi′an, China
                Author notes
                Correspondence to: Qingchuan Zhao, zhaoqc@ 123456fmmu.edu.cn
                Article
                20667
                10.18632/oncotarget.20667
                5669970
                29137344
                cfae4076-0a2f-4b07-aa2c-75717fd2f524
                Copyright: © 2017 Zhao et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 28 December 2016
                : 9 June 2017
                Categories
                Meta-Analysis

                Oncology & Radiotherapy
                nutrition,red meat,processed meat,colorectal cancer,meta-analysis
                Oncology & Radiotherapy
                nutrition, red meat, processed meat, colorectal cancer, meta-analysis

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