Platelet activation, aspirin, and cancer: From basic science to clinical trials

There is extensive evidence that aspirin prevents cancer, but the mechanism of action is uncertain. Once-daily low-dose aspirin (75-100 mg) completely and permanently inactivates the cyclooxygenase (COX) activity of prostaglandin G/H synthase-1 (COX-1) in platelets, suppressing thromboxane (TX)A₂-dependent platelet activation. In this article, we review the mechanistic links between platelet activation, inflammation, cancer development, and progression and summarize recent clinical trial results and associated biomarker studies. We hypothesize that persistently enhanced platelet activation has 2 distinct tumorigenic consequences mediated by the release of TXA₂: (1) at sites of gastrointestinal mucosal lesions, it promotes a local inflammatory response with COX-2 induction and enhanced prostaglandin E₂ biosynthesis, contributing to early events in carcinogenesis; (2) it inhibits T-cell immunity to cancer by the activation of TXA₂ receptors in lymphocytes, promoting cancer progression and metastasis dissemination. Supporting these hypotheses, abnormal and persistent platelet activation has been demonstrated in patients recently diagnosed with cancer and in those with adenomatous colonic polyps. To date, most clinical trials evaluating aspirin have focused on either primary cancer prevention, metastasis prevention (adjuvant treatment), or cardiovascular prevention. For an individual, benefits may accrue from one (or all) of these areas, and they collectively need to be balanced against bleeding risk. Collating large clinical datasets for meta-analysis alongside mechanistic studies will inform the interpretation of clinical trials, with the aim of identifying individuals most likely to benefit from aspirin. SIGNIFICANCE STATEMENT: We reviewed the experimental and clinical evidence supporting a previously unrecognized role of platelet activation in both the early stage of colorectal carcinogenesis and in cancer progression and metastasis. The findings support the use of low-dose aspirin in cancer prevention and treatment. Data from large randomized clinical trials support the use of aspirin for the prevention of Lynch syndrome cancers and in the adjuvant setting for patients with colorectal cancer whose tumors have a mutation in the phosphatidylinositol 3-kinase pathway genes. Although thromboxane A₂-dependent platelet activation is the most thoroughly investigated mechanism and the established drug target of the antiplatelet effect of low-dose aspirin, it seems biologically plausible that other pathways of platelet activation, such as the ADP-P2Y₁₂ pathway, may play a similar and possibly complementary role.