ReviewMechanism of colorectal carcinogenesis triggered by heme iron from red meat
Introduction
Colorectal cancer (CRC) ranks among the most frequent tumor entities worldwide with a global burden of around 1.8 Mio. people newly diagnosed for CRC every year [1]. Furthermore, an increasing incidence of CRC has recently been observed in adults under the age of fifty in both the US and Europe [2,3], highlighting the need to better understand the mechanism driving CRC formation in order to improve primary prevention. CRC is a multifactorial disease, which develops in the majority of cases sporadically due to acquired somatic mutations and aberrant epigenetic alterations in critical genes [1]. CRC is causally linked to life-style factors (e.g. alcohol, tobacco, physical inactivity) and dietary habits (e.g. red and processed meat intake, low dietary fiber) [1,4]. Epidemiological studies showed a clear association between meat consumption and CRC development [5,6]. In 2015, the International Agency for Research on Cancer classified the consumption of processed meat as carcinogenic and red meat as probably carcinogenic in humans [7]. A large prospective cohort study revealed that the intake of red meat also correlates with an increased risk for overall cancers, particularly breast cancer [8]. Red meat, e.g. beef and lamb, is characterized by its high myoglobin content and contains higher levels of heme iron as compared to white meat, such as chicken [9]. Interestingly, meta-analysis of epidemiological studies showed that dietary heme significantly increases the risk for CRC [10]. A recent prospective cohort study further supported this correlation and displayed a dose-effect relationship between heme iron uptake and the risk to develop colorectal adenoma [11]. A body of evidence suggests that heme iron is the critical component of red meat, which promotes colorectal carcinogenesis. In this review, we will provide a comprehensive overview on the underlying mechanisms known so far, involving, amongst others, genotoxic effects, hyperproliferation of the gut epithelium and changes in the intestinal microbiota. We will further highlight the impact of heme iron on immune cells and its possible link to CRC formation. It should be mentioned that also other red meat-derived agents might contribute to the elevated CRC risk. This comprises N-glycolylneuraminic acid (Neu5Gc), which is a sialic acid not occurring in humans. Neu5Gc was reported to cause systemic inflammation and to promote the progression of hepatocellular carcinoma in mice [12]. Furthermore, latent infections with the so-called bovine meat and milk factors (BMMF) and associated inflammatory processes might play a role in CRC etiology [13], particularly in the presence of food-borne carcinogens like N-nitroso compounds or heterocyclic aromatic amines [14,15].
Section snippets
Structure of heme
Heme is the prosthetic group of various proteins including the oxygen transporter proteins hemoglobin and myoglobin [16]. Hemoglobin consists of four subunits, two α- and two β-chains, which bind up to four oxygen molecules in the lung and transport them through the bloodstream to the tissue (Fig. 1). Due to the Bohr effect, the oxygen is transferred to the monomeric myoglobin in tissue consisting of only one β-chain [17]. The myoglobin then distributes the oxygen in the muscle, where it is
Gastrointestinal resorption of heme iron and inorganic iron
Iron is an essential micronutrient found in two dietary forms, heme iron and non-heme iron or inorganic iron. The latter occurs in vegetables and cereals, while the main nutritional source of heme iron represents animal tissue. Interestingly, heme iron has a greater bioavailability than non-heme iron [18]. Following its dietary uptake, heme is released from myoglobin and hemoglobin in the acidic environment of the stomach as well as by the proteolytic activity of different enzymes in the
Heme iron-mediated formation of genotoxic compounds and DNA damage induction
Heme iron gives rise to different DNA damaging agents, including reactive oxygen species (ROS), lipid peroxidation end-products and N-nitroso compounds (NOC).
Lipid peroxidation and cytotoxicity
As mentioned in the last chapter, dietary heme catalyzes lipid peroxidation and gives rise to reactive aldehydes, which are detected as TBARS. High levels of heme-induced TBARS in fecal water were associated with luminal injury and a high cytotoxicity if fecal water is applied to cultured colonocytes [21,36,63,103]. Further studies provided evidence that dietary heme decreases caspase-3 activity and inhibits apoptosis in the colon mucosa, which goes along with an increased proliferation and
Impact of heme on hyperproliferation
First evidence for an increased epithelial proliferation rate upon dietary heme intake was provided in a rodent feeding study by autoradiographic analysis of methyl-[3H]thymidine incorporation [21]. Interestingly, this effect could be blocked by dietary supplementation with high amounts of calcium [111]. Further short-term studies with moderate doses of heme (0.2 and 0.5 μmol/g diet) confirmed this finding, showing an increased number of Ki67-positive cells in colon crypts and an increased
Influence of heme iron on the intestinal microbiome
A growing body of evidence links the heme-induced hyperproliferation of colon epithelium to heme-dependent alterations of the gut flora. The intestinal microbiota plays a crucial role in host nutrient and drug metabolism, but also in maintaining the integrity of the gut mucosal barrier and in immunomodulation [116,117]. More than 90% of the gut microbiota is composed of four major phyla. The most prevailing phylum are gram-positive Firmicutes followed by gram-negative Bacteroidetes.
Modulation of immune cell function by heme
Dietary heme causes a microbial dysbiosis and impairs the intestinal barrier, thereby exposing the epithelium directly to enterobacteria and, thus, also bacterial lipopolysaccharides (LPS). Although one study reported no evidence for a Toll-like receptor 4 (TLR4)-triggered innate immune reaction and inflammation pathways in heme-fed mice [122], it is conceivable that bacteria reaching the epithelium will elicit an immune response and may promote intestinal inflammation. It is well-known that
Heme iron/red meat and intestinal tumorigenesis
Epidemiological studies provided evidence that the consumption of red meat and heme iron increases the risk to develop CRC (see Introduction). These data were supported by a series of experiments conducted in rodents, which were fed with a diet containing hemoglobin, hemin or other heme-rich meat sources. The first study indicating a contribution of heme iron to colon carcinogenesis was reported two decades ago [155]. The alkylating agent methylnitrosurea was administered intrarectally to rats
Concluding remarks
Several lines of evidence showed convincingly that heme iron, either free or bound as prosthetic group to hemoglobin or myoglobin, promotes CRC formation. Dietary heme exerts its pro-tumorigenic activity in the colorectum on multiple layers (Fig. 7) and thereby favors sporadic CRC formation, which is known to occur primarily via the adenoma-carcinoma sequence [1,163]. On the one hand, heme iron catalyzes the formation of genotoxic species and concomitant DNA damage induction. On the other hand,
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
This work was supported by the German Research Foundation (DFG FA1034/3-1 and FA1034/3-3).
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Present address: Department of Pharmacology, University Medical Center Mainz, 55131 Mainz, Germany.