Excess adiposity, which is increasingly a worldwide pathological condition, represents a major risk factor for most chronic diseases, including colorectal cancer (CRC).1 The third most common cancer in the world, CRC is also the fourth leading cause of cancer deaths.2 Furthermore, the World Health Organization projects steep increases in the number of deaths from CRC as populations age, with deaths from colon cancer increasing by 60.0% and those from rectal cancer increasing by 71.5% before 2035.2 To date, the best method of screening for CRC remains colonoscopy. However, colonoscopy presents patients with significant barriers that hinder compliance with screening. Barriers include costs and the extensive, days-long preparation for the exam itself, as well as patients’ logistics with time away from work and transportation, plus significant apprehension about the procedure itself. Unsurprisingly, compliance rates for patients with a history of polyps is as low as 15[ALH1] %.3 Nevertheless, the next-best alternative, the digital fecal occult blood test, is equally problematic, since as many as 10[ALH2] % of patients who test negative for CRC with the fecal occult blood test may actually have advanced neoplasias.4
No wonder, then, that researchers have aggressively pursued more accurate, noninvasive methods of screening for CRC. The answer may lie in detecting changes in lipid metabolism; specifically, changes in fatty acids.5 The main components of adipose tissue, fatty acids act as important modulators of inflammation, although the type of fatty acids stored in adipose tissue critically affects tissue functions.1 Fatty acids fall into 3 groups: saturated fatty acids, monosaturated fatty acids, and polyunsaturated fatty acids (PUFAs). According to a hypothesis in one recent study, the typical Western diet is rich in animal protein-derived saturated fatty acids.7 Now increasingly popular in the Pacific Rim, the Western diet, with its saturated fatty acids, may account for increasing levels of CRC.5 Moreover, significant correlations also exist between colon cancer and increased concentrations of monosaturated fatty acid in lipids, as well as with the trans-monosaturated fatty acids that result from diets rich in hydrogenated fats, in addition to consuming foods cooked or fried at temperatures >220°C.1
Although some of levels of fatty acids are both endogenous and exogenous,5 “[n]utrition seems to play a pivotal role in the onset and in the progression of gastrointestinal cancers, particularly of [CRC],” reported the authors of one study on the links between nutrition, lipids, and CRC.6 In fact, in one meta-analysis of studies linking diet and CRC, consumption of the Mediterranean diet, which is rich in PUFAS,7 decreased the risk for CRC by 18%, independent of other variables.7 Strikingly, even within PUFAs, different fatty acids have dramatically different effects. For example, although ω3 PUFA attenuates inﬂammation, ω6 PUFA is highly pro-inﬂammatory.8 In fact, lipid analyses from the sera of patients with CRC demonstrate a reduction of ω3 PUFA levels, as well as a higher ratio of ω6 PUFA:ω3 PUFA, in patients with CRC compared with healthy control individuals.9 Furthermore, increased concentrations of ω6 PUFAs found in the blood of patients with CRC may even help differentiate between early and advanced stages of CRC or act as prognostic indicators of survival.5 In addition, hydroxylated polyunsaturated ultra-long-chain fatty acids (hPULCFAs) also play a significant role in modulating intestinal inflammation, with lower levels of hPULCFAs, similar to levels of ω3 PUFAs and ω6 PUFAs, linked to high incidence rates of CRC.10
Early studies on the association between lipids and risk factors for CRC initially found associations only between ω3 PUFAs and CRC, with lower levels of ω3 PUFAs linked to large adenomas or progression from small to large adenomas.11 Recently, researchers have focused on lipids in sera, independent of diet, as potential biomarkers that identify patients’ risk factors for CRC. One study, focusing on hPULCFAs containing between 28 and 36 carbons, discovered significant reductions in hPULCFA levels in patients with CRC compared with healthy control individuals. In fact, this study’s statistical analyses reveal that the probability of reduced hPULCFA levels producing a false-positive for CRC is astronomically low.10 More recent studies have emphasized the roles of fatty acids from the ω6 PUFA family. These fatty acids, especially arachidonic acid, show pro-inflammatory properties, and thus, may act as tumor promoters.12 Furthermore, high dietary ratios ω6 PUFA:ω3 PUFA may be an important risk factor for other conditions resulting from chronic inflammation, including inflammatory bowel disease and nonalcoholic fatty liver disease.12,13 Several studies have confirmed ratios of ω6 PUFA:ω3 PUFA in cancerous tissue in patients with CRC that are significantly higher than levels even in normal tissue adjacent to adenomas.14,15
The future of screening for CRC may well lie in accurate, noninvasive screening of sera for alterations in lipids, especially focused on now-validated biomarkers that include levels of hPULCFA, ω3 PUFA, and ω6 PUFA. These promising lipid biomarkers may allow for earlier detection and treatment of CRC, as well as enhanced identification of its progression and patients’ prognosis.
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