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09-02-2017 | Image

Figure 2: The hypothesized inter-related mechanisms of aspirin chemoprevention.

Aspirin exerts its anticancer effects through several interconnected mechanisms: prostaglandin (PG) synthesis and catabolism in epithelial cells (lower left panel); inhibition of WNT–β-catenin signalling (lower right panel); and inactivation of platelets (upper right panel) and the host immune response (upper left panel). Through direct inhibition of prostaglandin-endoperoxide synthase 2 (PTGS2) at higher doses, aspirin blocks conversion of arachidonic acid to PGE2. Aspirin's effects may be enhanced by the expression of 15-hydroxyprostaglandin dehydrogenase (HPGD), a metabolic antagonist of PTGS2, through catabolism of PGE2 to PGE-M (the major metabolite of PGE2). PGE2 can activate WNT–β-catenin signalling through paracrine activation of EP2, its plasma membrane receptor. PGE2 can also activate cAMP and protein kinase A (PKA) signalling, further stabilizing cytosolic β-catenin. Aspirin can further inhibit β-catenin through inactivation of protein phosphatase 2A (PP2A), the phosphatase responsible for removing post-translational modifications that target β-catenin for ubiquitylation and subsequent destruction. In colorectal tumorigenesis, PTGS2 and β-catenin are upregulated, leading to increased cellular proliferation, growth and survival. Once in the nucleus, β-catenin forms a transcriptional activation complex with transcription factor 7 like-2 (TCF7L2) and activates effector genes with roles in tumorigenesis, such as MYC and PPARD (which encodes peroxisome proliferator-activated receptor-δ). Genetic variation at the single nucleotide polymorphism (SNP) rs6983267 may impair binding of the β-catenin–TCF7L2 complex to these transcriptional targets. The antiplatelet effects associated with low-dose aspirin are mediated through inhibition of PTGS1. PTGS1 converts arachidonic acid to thromboxane A2 (TXA2), the major metabolite promoting recruitment and activation of platelets. Platelets and inflammatory cells — especially infiltrating neutrophils and fibroblasts — recruited to the colonic epithelium in response to chronic inflammation or mucosal injury, may act as paracrine activators of PTGS2 in the colonic epithelium. The combined antiplatelet and anti-inflammatory effects of aspirin may specifically prevent inflammation-associated tumorigenesis, and aspirin may be particularly effective in individuals with increased circulating levels of inflammatory cytokines. Targets that are discussed as potential biomarkers that may have utility in risk stratification for precision chemoprevention are shown in red. CXCL1, C-X-C motif chemokine 1; IFNγ, interferon-γ; IL, interleukin; MIC1, macrophage inhibitory cytokine 1; PGT, prostaglandin transporter; sTNFR2, soluble TNF receptor 2; TNF, tumour necrosis factor.

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