**2.4 Processed meat**

*Multidisciplinary Approach for Colorectal Cancer*

**2.3 Red meat**

*2.3.1 Mechanism*

conjugated linoleic acid and butyric acid content [4].

modulate inflammatory responses [22]. Lactic acid-producing bacteria may also protect against CRC [20], while the casein and lactose in milk may increase calcium bioavailability [4, 23]. Lastly, the anticarcinogenic effect of milk is also related to its

There is strong probable evidence from epidemiologic studies that the consumption of red meat, including beef, pork, lamb, and goat from domesticated animals, increases the risk for developing CRC [7, 8]. The evidence for red meat has consistently shown a positive association in the dose-response meta-analyses for colorectal, colon, and rectal cancer. Despite the result being positive, it was not significant for colorectal and rectal cancers but significant for colon cancer. As there is evidence of plausible mechanisms operating in humans, the consumption of red meat is probably a cause of CRC [8]. In contrast to red meat, the consumption of poultry and fish has been associated with a modest reduction in CRC incidence. This is concordant with the concept that there are components other than fat and protein in red and processed meat that contribute to carcinogenic effects. Thus, based on current evidence, it would be reasonable to recommend the substitution of red and processed meat with poultry or fish, as it can serve as a strategy for CRC prevention [4].

Red meat consists of compounds such as haem iron (HI) that facilitates the endogenous formation of N-nitroso compounds (NOCs) such as nitrosylated HI, catalyzing its formation from natural precursors in the gastrointestinal tract (GI), as well as through lipid peroxidation in the GI [4, 24, 25]. In addition, HI can induce oxidative stress, colonocyte proliferation through the lipid-peroxidation pathway, and production of free radicals in the colonic stream [25]. The carcinogenic compounds forming during processing and cooking include NOCs and polycyclic aromatic hydrocarbons (PAHs) [25]. Cooking red or processed meat at high temperatures produces mutagens such as PAHs and heterocyclic aromatic amine (HAAs) [4, 25], both of which have been linked to CRC development in experimental studies [26]. The latter are genotoxic, and the extent to which HAAs' conversion to genotoxic metabolites occurs as a result of amino acids and creatinine reacting at high cooking temperatures is higher in humans than experimental animals. HAAs become DNA-alkylating agents, inducing DNA mutations after activation by various metabolizing enzymes. The GI microbiota adapts to meat intake and HAAs, resulting in HAAs possibly becoming more genotoxic in those with a high meat intake. However, the majority of studies that have investigated meat and phenotype interactions did not yield convincing evidence. It is therefore probable though that heat-induced mutagens found on the surface of well-done red meat can cause colon cancer in those with a genetic predisposition. NOCs, PAHs, and HAAs are considered to be genotoxic by acting directly on DNA, causing point mutations, deletions, and insertions. However, there is little direct evidence that these mechanisms come into play following meat consumption. A high consumption of HI (excluding other forms of iron), NOCs, HAAs, and PAHs has been associated with an increased risk of colorectal tumors, with a few exceptions. Genetic variations in NOCs' and HAAs' metabolism may alter the relationship between the consumption of red meat and the risk of developing colon cancer. However, there is substantial supporting mechanistic evidence regarding HI, NOCs, and HAAs being involved in colon carcinogenesis. A high consumption of red meat (300–420 g/day), increased levels of DNA adducts, is presumed to be derived from NOCs, in exfoliated

**12**

colonocytes or rectal biopsies [25].

There is strong convincing evidence that consuming processed meat, i.e., meats preserved by smoking, curing, or salting, or addition of chemical preservatives, increases the risk of CRC [7, 8]. The evidence is generally consistent by showing an increased risk of CRC with increased consumption of processed meat. The doseresponse meta-analysis showed a significant increased risk of CRC at consumption levels of 50 g/day [8].
