The crucial role of thromboxane A2 in colorectal cancer development and metastasis: a key target for anticancer therapy

Platelets play a crucial role in atherothrombosis, as demonstrated by the effectiveness of the antiplatelet agent aspirin (acetylsalicylic acid, ASA) in the secondary prevention of cardiovascular disease. Low-dose aspirin (75-100 mg/day) irreversibly and selectively inhibits cyclooxygenase (COX)-1 activity in platelets, thereby reducing thromboxane (TX)A(2)-dependent platelet activation. Recent evidence suggests that persistent platelet activation contributes to early carcinogenesis and metastasis progression by releasing TXA(2), which acts through two distinct mechanisms. First, by promoting inflammation at gastrointestinal mucosal lesions via induction of COX-2 and increased prostaglandin E-2 biosynthesis; second, by curbing T-cell-mediated anticancer immune responses. Therefore, inhibition of platelet TXA(2) biosynthesis is considered a central mechanism of aspirin's anticancer effects. Recent findings from large randomized clinical trials support its use in preventing Lynch syndrome cancers and as an adjuvant treatment in colorectal cancer patients with tumors carrying PI3K pathway mutations. However, it is important to note that aspirin and other conventional antiplatelet agents may increase the risk of bleeding. Novel antiplatelet agents are currently under development to achieve effective antiplatelet activity while minimizing bleeding. This review reports three possible options: PIM kinase inhibitors, protein disulfide isomerase inhibitors, and 12-lipoxygenase inhibitors. In conclusion, the discovery of novel roles for platelet TXA(2) in cancer paves the way for new therapeutic uses of low-dose aspirin and potentially other antiplatelet agents. Further research is needed to elucidate the mechanisms underlying aspirin's anticancer effects fully and to advance personalized treatment strategies. Furthermore, developing safer antiplatelet drugs will lead to therapeutic approaches for the primary prevention of cardiovascular disease and cancer.