Treg accumulation in tumors has been linked to either favorable or unfavorable clinical outcomes. 22 The contribution of Tregs to cancer progression is uncertain. 18 By using axozymethane (AOM)- and dextran sodium sulfate (DSS)-induced CRC in mice, a colitis-associated cancer (CAC) model, 19 it is possible to observe that the tumor microenvironment suppresses the immune response as the tumor progresses, 20 an effect mediated by the induction of distinct immunosuppressive cell types, including anti-inflammatory tumor-associated macrophages 21 and regulatory T (Treg) cells. 17 The precise mechanism of IBD-associated carcinogenesis is largely unknown, though it is generally assumed that it occurs as a result of an unbalanced gut mucosal inflammation/healing process caused by chronic inflammation. 14 In addition, the incidence of both IBD 15 and CRC 16 is increasing worldwide. 12Ĭlinical studies have shown that patients with ulcerative colitis (UC) are at 30% increased risk for developing CRC as compared to the general population. 12, 13 However, naturally occurring food components with high PPAR-γ activation potential have been neglected and less studied than pharmacological drugs. The discovery of PPAR-γ as the major functional receptor mediating the aminosalicylate activity in IBD treatment 10 and the impaired expression of PPAR-γ in IBD patients 11 have further enhanced the interest for the role of PPAR-γ in the regulation of gut homeostasis with possible therapeutic implications.
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7 The role of CLA in inflammatory bowel diseases (IBDs) 8 and colorectal cancer (CRC) 9 is an emerging field of research. 4 CLA is known as a potent agonist of peroxisome proliferator-activated receptor gamma (PPAR-γ) a nuclear receptor highly expressed in adipose tissue 5 immune cells 6 and gut enterocytes. 2, 3 Humans can convert a minor proportion of vaccenic acid into CLA.
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1 It is naturally found in meat and dairy products derived from ruminants and it can also be endogenously produced by the enzyme delta-9-desaturase desaturation. Thus, the anti-inflammatory properties of CLA are associated with prevention of colitis but also with development of colorectal cancer.Ĭonjugated linoleic acid (CLA) is a mixture of positional and geometric isomers of linoleic acid (LA). Accordingly, either macrophage-specific deletion of PPAR-γ or in vivo neutralization of latency-associated peptide (LAP, a membrane-bound TGF-β)-expressing cells abrogated the protumorigenic effect of CLA. However, CLA supplementation significantly worsened colorectal tumor formation induced by azoxymethane and DSS by inducing macrophage and T-cell-producing TGF-β via PPAR-γ activation.
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Conditional deletion of PPAR-γ in macrophages from mice supplemented with CLA diet resulted in loss of this protective effect of CLA, suggesting a PPAR-γ-dependent mechanism mediated by macrophages. We found that CLA-supplemented diet reduced mucosal damage and inflammatory infiltrate in the dextran sodium sulfate (DSS)-induced colitis model. Despite the worldwide use of CLA dietary supplementation, strong scientific evidence for its proposed beneficial actions are missing. Conjugated linoleic acid (CLA) has been shown to activate the nuclear receptor PPAR-γ and modulate metabolic and immune functions.