Aspirin affects early phases of metastasis through the inhibition of COX-1-thromboxane A2 axis

Thesis

Metastasis is the major cause of cancer related mortality, due to a poor understanding of the metastatic process and a subsequent lack of effective anti-metastatic therapies. Evidence from experimental studies and clinical trials has shown that aspirin reduces the incidence of distant metastases. It is well established that aspirin inhibits cyclooxygenase (COX)-1 and COX-2, triggering anti-thrombotic and anti-inflammatory effects, respectively. However, the mechanisms underlying the anti-metastatic effect of aspirin are still largely unknown.

By using an experimental model of pulmonary metastasis, we have found that the anti-metastatic effect of aspirin is associated with the inhibition of COX-1. In support of this, metastasis establishment was impaired in COX-1 deficient mice, suggesting a pivotal role of this isoform in the metastatic process. Looking in more detail into the metastatic cascade, we found that COX-1 contributes to the intravascular phase of metastasis and promotes the early persistence of tumour cells in the lung vasculature. In particular, COX-1 inhibition decreased the interaction of platelets with tumour cells and was associated with the reduction of endothelial activation, of tumour cell adhesion to the endothelium, of recruitment of metastasis-promoting monocytes/macrophages and of transendothelial migration. We have identified platelet-derived thromboxane A₂ (TXA₂) as the main product of COX-1 responsible for its permissive effect on metastasis. Indeed, TXA₂ delivered to mice in combination with aspirin was able to abrogate the anti-metastatic effect of aspirin.

Taken together, our data suggest that the inhibition of COX-1:TXA₂ axis by aspirin is sufficient to exert an anti-metastatic effect. In particular, the inhibition of platelet-derived TXA₂ seems to affect multiple early steps of the haematogenous transit of tumour cells. In this perspective, TXA₂ might represent a more selective therapeutic target for the prevention of metastasis.

Authors: Lucotti, S

• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: Metastasis; COX-1; Platelets; Thromboxane A2; Aspirin