The Role and Regulation of Thromboxane A(2) Signaling in Cancer-Trojan Horses and Misdirection

Over the last two decades, there has been an increasing awareness of the role of eicosanoids in the development and progression of several types of cancer, including breast, prostate, lung, and colorectal cancers. Several processes involved in cancer development, such as cell growth, migration, and angiogenesis, are regulated by the arachidonic acid derivative thromboxane A(2) (TXA(2)). Higher levels of circulating TXA(2) are observed in patients with multiple cancers, and this is accompanied by overexpression of TXA(2) synthase (TBXAS1, TXA(2)S) and/or TXA(2) receptors (TBXA2R, TP). Overexpression of TXA(2)S or TP in tumor cells is generally associated with poor prognosis, reduced survival, and metastatic disease. However, the role of TXA(2) signaling in the stroma during oncogenesis has been underappreciated. TXA(2) signaling regulates the tumor microenvironment by modulating angiogenic potential, tumor ECM stiffness, and host immune response. Moreover, the by-products of TXA(2)S are highly mutagenic and oncogenic, adding to the overall phenotype where TXA(2) synthesis promotes tumor formation at various levels. The stability of synthetic enzymes and receptors in this pathway in most cancers (with few mutations reported) suggests that TXA(2) signaling is a viable target for adjunct therapy in various tumors to reduce immune evasion, primary tumor growth, and metastasis.