Aspirin and colorectal cancer: the promise of precision chemoprevention

Abstract

Aspirin (acetylsalicylic acid) has become one of the most commonly used drugs, given its role as an analgesic, antipyretic and agent for cardiovascular prophylaxis. Several decades of research have provided considerable evidence demonstrating its potential for the prevention of cancer, particularly colorectal cancer. Broader clinical recommendations for aspirin-based chemoprevention strategies have recently been established; however, given the known hazards of long-term aspirin use, larger-scale adoption of an aspirin chemoprevention strategy is likely to require improved identification of individuals for whom the protective benefits outweigh the harms. Such a precision medicine approach may emerge through further clarification of aspirin's mechanism of action.

Figure 1 |. Timeline of notable human studies in aspirin chemoprevention.

Decades of research have substantially clarified the anticancer effect associated with the use of aspirin. Recent compelling human data have also influenced the United States Preventive Services Task Force (USPSTF) to support the use of aspirin for the primary prevention of colorectal cancer (CRC) in certain subgroups of the US population. Asterisks indicate trials that are ongoing and have an unknown end date. ABC, Aspirin and the Biology of the Colon; AFPPS, Aspirin/Folate Polyp Prevention Study; APACC, Association pour la Prévention par l’Aspirine du Cancer Colorectal; ARRIVE, Aspirin to Reduce Risk of Initial Vascular Events; ASCOLT, Aspirin for Dukes C and High Risk Dukes B Colorectal Cancers; ASPREE, ASPirin in Reducing Events in the Elderly; ASPIRED, ASPirin Intervention for the REDuction of colorectal cancer risk; CALGB, Colorectal Adenoma prevention study originated in the cooperative trials group cancer and Leukaemia Group B; CAPP, Colorectal Adenoma/carcinoma Prevention Programme; CPS-II, Cancer Prevention Study II; CVD, cardiovascular disease; GxE, gene by environment; HPFS, Health Professionals Follow-up Study; HPGD, 15-hydroxyprostaglandin dehydrogenase; J-CAPP, Japan Colorectal Aspirin Polyps Prevention; J-FAPP, Japan Familial Adenomatous Polyposis Prevention; NHS, Nurses’ Health Study; NSAID, non-steroidal anti-inflammatory drug; PGE-M, major metabolite of prostaglandin E₂; PHS, Physicians’ Health Study; PIK3CA, PI3K catalytic subunit-α; PTGS2, prostaglandin-endoperoxide synthase 2; RCT, randomized clinical trial; seAFOod, Systematic Evaluation of Aspirin and Fish Oil; sTNFR2, soluble TNF receptor 2; ukCAP, United Kingdom Colorectal Adenoma Prevention; WHS, Women’s Health Study.

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.